Imidazoyl pyridine compounds and salts thereof

ABSTRACT

A compound represented by the formula (I): 
                         
or a pharmacologically acceptable salt thereof, wherein Ar 1  represents an imidazolyl group or the like which may be substituted with a C1-6 alkyl group, Ar 2  represents a phenyl group or the like which may be substituted with a C1-6 alkoxy group, X 1  represents a double bond or the like and Het represents a triazolyl group or the like which may be substituted with a C1-6 alkyl group or the like, is effective as a therapeutic or prophylactic agent for a disease caused by Aβ.

RELATED APPLICATIONS

The present application claims priority from U.S. provisionalapplication Ser. No. 60/935,824 filed on Aug. 31, 2007, U.S. provisionalapplication Ser. No. 61/025,099 filed on Jan. 31, 2008 and U.S.provisional application Ser. No. 61/051,751 filed on May 9, 2008, all ofthe contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Filed of the Invention

The present invention relates to a pharmaceutical, more particularly, toa multi-cyclic cinnamide derivative effective for treatment of aneurodegenerative disease caused by amyloid-β (hereinafter referred toas Aβ) such as Alzheimer's disease or Down's syndrome and a medicine, inparticular, a medicine for prevention or treatment of a disease causedby Aβ comprising the derivative as an active ingredient.

2. Description of Related Art

Alzheimer's disease is a disease characterized by degeneration and lossof neurons as well as formation of senile plaques and neurofibrillarydegeneration. Currently, Alzheimer's disease is treated only withsymptomatic treatment using a symptom improving agent typified by anacetylcholinesterase inhibitor, and a fundamental remedy to inhibitprogression of the disease has not yet been developed. It is necessaryto develop a method for controlling the cause of the onset of pathologyin order to create a fundamental remedy for Alzheimer's disease.

It is assumed that Aβ-proteins as metabolites of amyloid precursorproteins (hereinafter referred to as APP) are highly involved indegeneration and loss of neurons and onset of symptoms of dementia (seeNon-Patent Documents 1 and 2, for example). Main molecular species ofAβ-protein are Aβ40 consisting of 40 amino acids and Aβ42 with two aminoacids added at the C-terminal. The Aβ40 and Aβ42 are known to have highaggregability (see Non-Patent Document 3, for example) and to be maincomponents of senile plaques (see Non-Patent Documents 3, 4 and 5, forexample). Further, it is known that the Aβ40 and Aβ42 are increased bymutation in APP and presenilin genes which is observed in familialAlzheimer's disease (see Non-Patent Documents 6, 7 and 8, for example).Accordingly, a compound that reduces production of Aβ40 and Aβ42 isexpected as a progression inhibitor or prophylactic agent forAlzheimer's disease.

Aβ is produced by cleaving APP by β-secretase and subsequently byγ-secretase. For this reason, attempts have been made to createγ-secretase and β-secretase inhibitors in order to reduce Aβ production.Many of these secretase inhibitors already known are, for example,peptides and peptide mimetics such as L-685,458 (see Non-Patent Document9, for example), LY-411,575 (see Non-Patent Documents 10, 11 and 12, forexample) and LY-450,139 (see Non-Patent Documents 13, 14 and 15).Nonpeptidic compounds are, for example, MRK-560 (see Non-PatentDocuments 16 and 17) and compounds having a plurality of aromatic ringsas disclosed in Patent Document 1. However, the compound represented bythe formula (VI) as disclosed in page 17 of the specification differsfrom the compound of the present invention in that the compound islimited to a compound having a 2-aminothiazolyl group as a mainstructure.

-   [Non-Patent Document 1] Klein W L, and seven others, Alzheimer's    disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs)    suggests a molecular basis for reversible memory loss, Proceeding of    the National Academy of Science USA, Sep. 2, 2003; 100(18), p.    10417-10422.-   [Non-Patent Document 2] Nitsch R M, and sixteen others, Antibodies    against β-amyloid slow cognitive decline in Alzheimer's disease,    Neuron, May 22, 2003; 38, p. 547-554.-   [Non-Patent Document 3] Jarrett J T, and two others, The carboxy    terminus of the β amyloid protein is critical for the seeding of    amyloid formation: Implications for the pathogenesis of Alzheimers'    disease, Biochemistry, 1993, 32(18), p. 4693-4697.-   [Non-Patent Document 4] Glenner G G, and one other, Alzheimer's    disease: initial report of the purification and characterization of    a novel cerebrovascular amyloid protein, Biochemical and Biophysical    Research Communications, May 16, 1984, 120(3), p. 885-890.-   [Non-Patent Document 5] Masters C L, and five others, Amyloid plaque    core protein in Alzheimer disease and Down syndrome, Proceeding of    the National Academy of Science USA, June, 1985, 82(12), p.    4245-4249.-   [Non-Patent Document 6] Gouras G K, and eleven others, Intraneuronal    Aβ42 accumulation in human brain, American Journal of Pathology,    January, 2000, 156(1), p. 15-20.-   [Non-Patent Document 7] Scheuner D, and twenty others, Secreted    amyloid β-protein similar to that in the senile plaques of    Alzheimer's disease is increased in vivo by the presenilin 1 and 2    and APP mutations linked to familial Alzheimer's disease, Nature    Medicine, August, 1996, 2(8), p. 864-870.-   [Non-Patent Document 8] Forman M S, and four others, Differential    effects of the swedish mutant amyloid precursor protein on β-amyloid    accumulation and secretion in neurons and nonneuronal cells, The    Journal of Biological Chemistry, Dec. 19, 1997, 272(51), p.    32247-32253.-   [Non-Patent Document 9] Shearman M S, and nine others, L-685, 458,    an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor    of Amyloid β-Protein Precursor γ-Secretase Activity, Biochemistry,    Aug. 1, 2000, 39(30), p. 8698-8704.-   [Non-Patent Document 10] Shearman M S, and six others, Catalytic    Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate    Pharmacologically between Notch S3 and β-APP Clevages, Biochemistry,    Jun. 24, 2003, 42(24), p. 7580-7586.-   [Non-Patent Document 11] Lanz T A, and three others, Studies of Aβ    pharmacodynamics in the brain, cerebrospinal fluid, and plasma in    young (plaque-free) Tg2576 mice using the γ-secretase inhibitor    N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide    (LY-411575), The Journal of Pharmacology and Experimental    Therapeutics, April, 2004, 309(1), p. 49-55.-   [Non-Patent Document 12] Wong G T, and twelve others, Chronic    treatment with the γ-secretase inhibitor LY-411, 575 inhibits    β-amyloid peptide production and alters lymphopoiesis and intestinal    cell differentiation, The Journal of Biological Chemistry, Mar. 26,    2004, 279(13), p. 12876-12882.-   [Non-Patent Document 13] Gitter B D, and ten others, Stereoselective    inhibition of amyloid beta peptide secretion by LY450139, a novel    functional gamma secretase inhibitor, Neurology of Aging 2004, 25,    sup2, p. 571.-   [Non-Patent Document 14] Lanz T A, and eighteen others,    Concentration-dependent modulation of amyloid-β in vivo and in vitro    using the γ-secretase inhibitor, LY-450139, The Journal of    Pharmacology and Experimantal Therapeutics, November, 2006,    319(2) p. 924-933.-   [Non-Patent Document 15] Siemers E R, and thirteen others, Effects    of a γ-secretase inhibitor in a randomized study of patients with    Alzheimer disease, Neurology, 2006, 66, p. 602-604.-   [Non-Patent Document 16] Best J D, and nine others, In vivo    characterization of Aβ (40) changes in brain and cerebrospinal fluid    using the novel γ-secretase inhibitor    N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulphonlamide    (MK-560) in the rat, The Journal of Pharmacology and Experimantal    Therapeutics, May, 2006, 317(2) p. 786-790.-   [Non-Patent Document 17] Best J D, and thirteen others The novel    γ-secretase inhibitor    N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulphonlamide    (MK-560) reduces amylid plaque deposition without evidence    notch-related pathology in the Tg2576 mouse, The Journal of    Pharmacology and Experimantal Therapeutics, February, 2007,    320(2) p. 552-558.-   [Patent Document 1] WO 2004/110350

BRIEF SUMMARY OF THE INVENTION

As described above, a compound that inhibits production of Aβ40 and Aβ42from APP has been expected as a therapeutic or prophylactic agent for adisease caused by Aβ which is typified by Alzheimer's disease. However,a nonpeptidic compound having high efficacy which inhibits production ofAβ40 and Aβ42 has not yet been known. Accordingly, there is a need for anovel low-molecular-weight compound that inhibits production of Aβ40 andAβ42.

As a result of extensive studies, the present inventors have found anonpeptidic multi-cyclic compound that inhibits production of Aβ40 andAβ42 from APP and thus found a prophylactic or therapeutic agent for adisease caused by Aβ which is typified by Alzheimer's disease. Thisfinding has led to the accomplishment of the present invention.

Specifically, the present invention relates to the following 1) to 19):

-   1) A compound represented by the formula (I):

or a pharmacologically acceptable salt thereof, wherein Ar₁ representsan imidazolyl group which may be substituted with a C1-6 alkyl group,

-   Ar₂ represents a phenyl group or a pyridinyl group, which may be    substituted with 1 to 3 substituents selected from the group    consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a    hydroxyl group and (4) a C1-6 alkoxy group,-   X₁ represents —CR¹═CR²— (wherein R¹ and R² are the same or different    and each represent (1) a hydrogen atom, (2) a C1-6 alkyl group    or (3) a halogen atom) and Het is monovalent or divalent and    represents (1) a 5-membered aromatic heterocyclic group, (2) a    5-membered aromatic heterocyclic group condensed with a 6- to    14-membered non-aromatic hydrocarbon ring group or (3) a 5-membered    aromatic heterocyclic group condensed with a 5- to 14-membered    non-aromatic heterocyclic group, which may be substituted with 1 to    3 substituents selected from the following Substituent Group A1-   [Substituent Group A1: (1) a hydrogen atom, (2) a halogen atom, (3)    a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8    cycloalkyl group which may be substituted with 1 to 3 substituents    selected from Substituent Group A2, (7) a C2-6 alkenyl group which    may be substituted with 1 to 3 substituents selected from    Substituent Group A2, (8) a C2-6 alkynyl group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A2, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio    group, (11) a formyl group, (12) a C1-6 alkylcarbonyl group which    may be substituted with 1 to 3 substituents selected from    Substituent Group A2, (13) a C1-6 alkylthio group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A2, (14) a C1-6 alkylsulfinyl group which may be substituted with 1    to 3 substituents selected from Substituent Group A2, (15) a C1-6    alkylsulfonyl group which may be substituted with 1 to 3    substituents selected from Substituent Group A2, (16) a hydroxyimino    group, (17) a C1-6 alkoxyimino group, (18) a C1-6 alkyl group which    may be substituted with 1 to 3 substituents selected from    Substituent Group A2, (19) a C1-6 alkoxy group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A2, (20) an amino group which may be substituted with 1 or 2    substituents selected from Substituent Group A2, (21) a carbamoyl    group which may be substituted with 1 or 2 substituents selected    from Substituent Group A2, (22) a 6- to 14-membered aromatic    hydrocarbon ring group which may be substituted with 1 to 3    substituents selected from Substituent Group A2, (23) a 5- to    14-membered aromatic heterocyclic group which may be substituted    with 1 to 3 substituents selected from Substituent Group A2, (24) a    6- to 14-membered non-aromatic hydrocarbon ring group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A2, (25) a 5- to 14-membered non-aromatic heterocyclic group which    may be substituted with 1 to 3 substituents selected from    Substituent Group A2, (26) a C2-6 alkenyloxy group, (27) a C2-6    alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8    cycloalkylsulfonyl group, (30) —X-A (wherein X represents an imino    group, —O— or —S— and A represents a 6- to 14-membered aromatic    hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic    group which may be substituted with 1 to 3 substituents selected    from Substituent Group A2), (31) —CO-A (wherein A is as defined    above), (32) ═CH-A (wherein A is as defined above), (33) a carboxyl    group, (34) a C1-6 alkoxycarbonyl group and (35) an azido group;    Substituent Group A2: (1) a hydrogen atom, (2) a halogen atom, (3) a    hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8    cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl    group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio    group, (11) a formyl group, (12) a C1-6 alkylcarbonyl group, (13) a    C1-6 alkylthio group, (14) a C1-6 alkylsulfinyl group, (15) a C1-6    alkylsulfonyl group, (16) a hydroxyimino group, (17) a C1-6    alkoxyimino group, (18) a C1-6 alkyl group (wherein the C1-6 alkyl    group may be substituted with 1 to 3 substituents selected from the    group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy    group, a phenyl group which may be substituted with 1 to 3 halogen    atoms and a pyridinyl group which may be substituted with 1 to 3    halogen atoms), (19) a C1-6 alkoxy group (wherein the C1-6 alkoxy    group may be substituted with 1 to 3 substituents selected from the    group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy    group, a phenyl group which may be substituted with 1 to 3 halogen    atoms and a pyridinyl group which may be substituted with 1 to 3    halogen atoms), (20) an amino group which may be substituted with 1    or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups, (21) a    carbamoyl group which may be substituted with 1 or 2 C1-6 alkyl    groups, (22) a 6- to 14-membered aromatic hydrocarbon ring    group, (23) a 5- to 14-membered aromatic heterocyclic group, (24) a    6- to 14-membered non-aromatic hydrocarbon ring group, (25) a 5- to    14-membered non-aromatic heterocyclic group, (26) a C2-6 alkenyloxy    group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl    group, (29) a C3-8 cycloalkylsulfonyl group, (30) —X-A′ (wherein X    represents an imino group, —O—, —S— or —SO₂— and A′ represents a 6-    to 14-membered aromatic hydrocarbon ring group or a 5- to    14-membered aromatic heterocyclic group which may be substituted    with 1 to 3 halogen atoms), (31) —CO-A′ (wherein A′ is as defined    above) and (32) ═CH-A′ (wherein A′ is as defined above)];-   2) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein the compound is represented by the    formula (I-1), (I-2) or (I-3):

wherein X₁ and Het are as defined above;

-   3) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein the compound is represented by the    formula (I-1) or (I-3);-   4) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein the compound is represented by the    formula (I-1);-   5) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein X₁ represents —CR¹═CR²— (wherein R¹    and R² are the same or different and each represent a hydrogen atom    or a fluorine atom;-   6) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein X₁ represents —CH═CH—;-   7) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein Het represents a triazolyl group    which may be substituted with 1 or 2 substituents selected from    Substituent Group A1;-   8) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein Het represents a group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A1 and is represented by the following formula:

wherein R³ and R⁴ are the same or different and each represent asubstituent selected from Substituent Group A1, or R³ and R⁴ are takentogether with a carbon atom to which they are bonded to form ═CH-A(wherein A represents a 6- to 14-membered aromatic hydrocarbon ringgroup or a 5- to 14-membered aromatic heterocyclic group which may besubstituted with 1 to 3 substituents selected from Substituent GroupA2), X₂ represents a methylene group which may be substituted with asubstituent selected from Substituent Group A1, or an oxygen atom andn_(a) represents an integer of 0 to 2;

-   9) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein Het represents a group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A1 and is represented by the following formula:

wherein R⁵ and R⁶ are the same or different and each represent asubstituent selected from Substituent Group A1, X₃ represents amethylene group which may be substituted with a substituent selectedfrom Substituent Group A1, or an oxygen atom and n_(b) represents aninteger of 0 to 2;

-   10) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein Het represents a group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A1 and is represented by the following formula:

wherein n_(c) represents an integer of 0 to 3;

-   11) The compound or pharmacologically acceptable salt thereof    according to 6) above, wherein n_(c) represents 0 or 2;-   12) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein Het represents a group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A1 and is represented by the following formula:

wherein n_(d) represents an integer of 0 to 3;

-   13) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein Het represents a group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A1 and is represented by the following formulas:

wherein R³ and R⁴ are as defined above;

-   The compound or pharmacologically acceptable salt thereof according    to 1) above, wherein Substituent Group A1 is a group consisting    of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl    group, (4) a cyano group, (5) a C3-8 cycloalkyl group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A2, (6) a C1-6 alkyl group which may be substituted with 1 to 3    substituents selected from Substituent Group A2, (7) a 6- to    14-membered aromatic hydrocarbon ring group which may be substituted    with 1 to 3 substituents selected from Substituent Group A2, (8) a    5- to 14-membered aromatic heterocyclic group which may be    substituted with 1 to 3 substituents selected from Substituent Group    A2, (9) a 6- to 14-membered non-aromatic hydrocarbon ring group    which may be substituted with 1 to 3 substituents selected from    Substituent Group A2, (10) a 5- to 14-membered non-aromatic    heterocyclic group which may be substituted with 1 to 3 substituents    selected from Substituent Group A2, (11) —X-A (wherein X represents    an imino group, —O— or —S— and A represents a 6- to 14-membered    aromatic hydrocarbon ring group or a 5- to 14-membered aromatic    heterocyclic group, which may be substituted with 1 to 3    substituents selected from Substituent Group A2), (12) ═CH-A    (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring    group or a 5- to 14-membered aromatic heterocyclic group, which may    be substituted with 1 to 3 substituents selected from Substituent    Group A2) and (13) an azido group;-   The compound or pharmacologically acceptable salt thereof according    to 1) above, wherein Substituent Group A2 is a group consisting    of (1) a hydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group    (wherein the C1-6 alkyl group may be substituted with 1 to 3    substituents selected from the group consisting of a halogen atom    and a C1-6 alkoxy group) and (4) a C1-6 alkoxy group (wherein the    C1-6 alkoxy group may be substituted with a halogen atom);-   16) The compound or pharmacologically acceptable salt thereof    according to 1) above, wherein the compound is selected from the    following group:-   1)    (−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   2)    (−)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   3)    (−)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   4)    (−)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol,-   5)    (+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,-   6)    8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   7)    8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   8)    (−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole,-   9)    (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[1,5-a]pyridine,-   10)    (−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   11)    (−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   12)    (−)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   13)    (+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   14)    (+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   15)    (−)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   16)    (−)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   17)    (+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   18)    (−)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   19)    (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   20)    (+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   21)    (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   22)    (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   23)    (+)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   24)    (−)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   25)    (+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   26)    (−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile,-   27)    (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine,-   28)    (−)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   29)    (−)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   30)    (−)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   31)    (−)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   32)    (−)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   33)    (−)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine    and-   34)    (−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   35)    (−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   36)    (−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,-   37)    (−)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   38)    (5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   39)    (S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,    and-   40)    (S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole;-   17) A medicine comprising the compound or pharmacologically    acceptable salt thereof according to any of 1) to 16) above as an    active ingredient;-   18) The medicine according to 17) above for preventing or treating a    disease caused by amyloid-β; and-   19) The medicine according to 18) above, wherein the disease caused    by amyloid-β is Alzheimer's disease, dementia, Down's syndrome or    amyloidosis.

The compound of the general formula (I) or pharmacologically acceptablesalt thereof according to the present invention and the prophylactic ortherapeutic agent for a disease caused by Aβ according to the presentinvention are novel inventions that have not yet been described in anydocuments.

Meanings of symbols, terms and the like used in the presentspecification will be explained and the present invention will bedescribed in detail below.

In the present specification, a structural formula of a compound mayrepresent a certain isomer for convenience. However, the presentinvention includes all isomers and isomer mixtures such as geometricisomers which can be generated from the structure of a compound, opticalisomers based on asymmetric carbon, stereoisomers and tautomers. Thepresent invention is not limited to the description of a chemicalformula for convenience and may include any one of the isomers ormixtures thereof. Accordingly, the compound of the present invention mayhave an asymmetric carbon atom in the molecule and exist as an opticallyactive compound or racemate, and the present invention includes each ofthe optically active compound and the racemate without limitations.Although crystal polymorphs of the compound may be present, the compoundis not limited thereto as well and may be present as a single crystalform or a mixture of single crystal forms. The compound may be ananhydride or hydrate.

The “disease caused by Aβ” refers to a wide variety of diseases such asAlzheimer's disease (see, for example, Klein W L, and seven others,Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands(ADDLs) suggests a molecular basis for reversible memory loss,Proceeding National Academy of Science USA, Sep. 2, 2003, 100(18), p.10417-10422; Nitsch R M, and sixteen others, Antibodies againstβ-amyloid slow cognitive decline in Alzheimer's disease, Neuron, May 22,2003, 38(4), p. 547-554: Jarrett J T, and two others, The carboxyterminus of the β amyloid protein is critical for the seeding of amyloidformation: Implications for the pathogenesis of Alzheimers' disease,Biochemistry, May 11, 1993, 32(18), p. 4693-4697; Glenner G G, and oneother, Alzheimer's disease; initial report of the purification andcharacterization of a novel cerebrovascular amyloid protein, Biochemicaland biophysical research communications, May 16, 1984, 120(3), p.885-890; Masters C L, and six others, Amyloid plaque core protein inAlzheimer disease and Down syndrome, Proceeding National Academy ofScience USA, June, 1985, 82(12), p. 4245-4249; Gouras G K, and elevenothers, Intraneuronal Aβ42 accumulation in human brain, American journalof pathology, January, 2000, 156(1), p. 15-20; Scheuner D, and twentyothers, Secreted amyloid β-protein similar to that in the senile plaquesof Alzheimer's disease is increased in vivo by the presenilin 1 and 2and APP mutations linked to familial Alzheimer's disease, NatureMedicine, August, 1996, 2(8), p. 864-870; Forman M S, and four others,Differential effects of the swedish mutant amyloid precursor protein onβ-amyloid accumulation and secretion in neurons and nonneuronal cells,The journal of biological chemistry, Dec. 19, 1997, 272(51), p.32247-32253), senile dementia (see, for example, Blass J P, Brainmetabolism and brain disease: Is metabolic deficiency the proximatecause of Alzheimer dementia? Journal of Neuroscience Research, Dec. 1,2001, 66(5), p. 851-856), frontotemporal dementia (see, for example,Evin G, and eleven others, Alternative transcripts of presenilin-1associated with frontotemporal dementia, Neuroreport, Apr. 16, 2002,13(5), p. 719-723), Pick's disease (see, for example, Yasuhara O, andthree others, Accumulation of amyloid precursor protein in brain lesionsof patients with Pick disease, Neuroscience Letters, Apr. 25, 1994,171(1-2), p. 63-66), Down's syndrome (see, for example, Teller J K, andten others, Presence of soluble amyloid β-peptide precedes amyloidplaque formation in Down's syndrome, Nature Medicine, January, 1996,2(1), p. 93-95; Tokuda T, and six others, Plasma levels of amyloid βproteins Aβ1-40 and Aβ1-42(43) are elevated in Down's syndrome, Annalsof Neurology, February, 1997, 41(2), p. 271-273), cerebral angiopathy(see, for example, Hayashi Y, and nine others, Evidence for presenilin-1involvement in amyloid angiopathy in the Alzheimer's disease-affectedbrain, Brain Research, Apr. 13, 1998, 789(2), p. 307-314; Barelli H, andfifteen others, Characterization of new polyclonal antibodies specificfor 40 and 42 amino acid-long amyloid β peptides: their use to examinethe cell biology of presenilins and the immunohistochemistry of sporadicAlzheimer's disease and cerebral amyloid angiopathy cases, MolecularMedicine, October, 1997, 3(10), p. 695-707; Calhoun M E, and ten others,Neuronal overexpression of mutant amyloid precursor protein results inprominent deposition of cerebrovascular amyloid, Proceeding NationalAcademy of Science USA, Nov. 23, 1999, 96(24), p. 14088-14093; DermautB, and ten others, Cerebral amyloid angiopathy is a pathogenic lesion inAlzheimer's Disease due to a novel presenilin-1 mutation, Brain,December, 2001, 124(12), p. 2383-2392), hereditary cerebral hemorrhagewith amyloidosis (Dutch type) (see, for example, Cras P, and nineothers, Presenile Alzheimer dementia characterized by amyloid angiopathyand large amyloid core type senile plaques in the APP 692Ala→Glymutation, Acta Neuropathologica (Berl), September, 1998, 96(3), p.253-260; Herzig M C, and fourteen others, Aβ is targeted to thevasculature in a mouse model of hereditary cerebral hemorrhage withamyloidosis, Nature Neuroscience, 2004, September, 7(9), p. 954-960; vanDuinen S G, and five others, Hereditary cerebral hemorrhage withamyloidosis in patients of Dutch origin is related to Alzheimer disease,Proceeding National Academy of Science USA, August, 1987, 84(16), p.5991-5994; Levy E, and eight others, Mutation of the Alzheimer's diseaseamyloid gene in hereditary cerebral hemorrhage, Dutch type, Science,Jun. 1, 1990, 248(4959), p. 1124-1126), cognitive impairment (see, forexample, Laws S M, and seven others, Association between thepresenilin-1 mutation Glu318Gly and complaints of memory impairment,Neurobiology of Aging, January-February, 2002, 23(1), p. 55-58),dysmnesia and learning disability (see, for example, Vaucher E, and fiveothers, Object recognition memory and cholinergic parameters in miceexpressing human presenilin 1 transgenes, Experimental Neurology, June2002, 175(2), p. 398-406; Morgan D, and fourteen others, Aβ peptidevaccination prevents memory loss in an animal model of Alzheimer'sdisease, Nature, Dec. 21-28, 2000, 408(6815), p. 982-985; Moran P M, andthree others, Age-related learning deficits in transgenic miceexpressing the 751-amino acid isoform of human β-amyloid precursorprotein, Proceeding National Academy of Science USA, Jun. 6, 1995,92(12), p. 5341-5345), amyloidosis, cerebral ischemia (see, for example,Laws S M, and seven others, Association between the presenilin-1mutation Glu318Gly and complaints of memory impairment, Neurobiology ofAging, January-February, 2002, 23(1), p. 55-58; Koistinaho M, and tenothers, β-amyloid precursor protein transgenic mice that harbor diffuseAβ deposits but do not form plaques show increased ischemicvulnerability: Role of inflammation, Proceeding National Academy ofScience USA, Feb. 5, 2002, 99(3), p. 1610-1615; Zhang F, and fourothers, Increased susceptibility to ischemic brain damage in transgenicmice overexpressing the amyloid precursor protein, The journal ofneuroscience, Oct. 15, 1997, 17(20), p. 7655-7661), vascular dementia(see, for example, Sadowski M, and six others, Links between thepathology of Alzheimer's disease and vascular dementia, NeurochemicalResearch, June, 2004, 29(6), p. 1257-1266), ophthalmoplegia (see, forexample, O'Riordan S, and seven others, Presenilin-1 mutation (E280G),spastic paraparesis, and cranial MRI white-matter abnormalities,Neurology, Oct. 8, 2002, 59(7), p. 1108-1110), multiple sclerosis (see,for example, Gehrmann J, and four others, Amyloid precursor protein(APP) expression in multiple sclerosis lesions, Glia, October, 1995,15(2), p. 141-51; Reynolds W F, and six others, Myeloperoxidasepolymorphism is associated with gender specific risk for Alzheimer'sdisease, Experimental Neurology, January, 1999, 155(1), p. 31-41), headinjury, skull injury (see, for example, Smith D H, and four others,Protein accumulation in traumatic brain injury, NeuroMolecular Medicine,2003, 4(1-2), p. 59-72), apraxia (see, for example, Matsubara-Tsutsui M,and seven others, Molecular evidence of presenilin 1 mutation infamilial early onset dementia, American journal of Medical Genetics,Apr. 8, 2002, 114(3), p. 292-298), prion disease, familial amyloidneuropathy, triplet repeat disease (see, for example, Kirkitadze M D,and two others, Paradigm shifts in Alzheimer's disease and otherneurodegenerative disorders: the emerging role of oligomeric assemblies,Journal of Neuroscience Research, Sep. 1, 2002, 69(5), p. 567-577; EvertB O, and eight others, Inflammatory genes are upreglulated in expandedataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains,The Journal of Neuroscience, Aug. 1, 2001, 21(15), p. 5389-5396; Mann DM, and one other, Deposition of amyloid (A4) protein within the brainsof persons with dementing disorders other than Alzheimer's disease andDown's syndrome, Neuroscience Letters, Feb. 5, 1990, 109(1-2), p.68-75), Parkinson's disease (see, for example, Primavera J, and fourothers, Brain accumulation of amyloid-β in Non-AlzheimerNeurodegeneration, Jornal of Alzheimer's Disease, October, 1999, 1(3),p. 183-193), Lewy body dementia (see, for example, Giasson B I, and twoothers, Interactions of amyloidogenic proteins. NeuroMolecular Medicine,2003, 4(1-2), p. 49-58; Masliah E, and six others, β-amyloid peptidesenhance α-synuclein accumulation and neuronal deficits in a trancgenicmouse model linking Alzheimer's disease and Parkinson's disease,Proceeding National Academy of Science USA, Oct. 9, 2001, 98(21), p.12245-12250; Barrachina M, and six others, Amyloid-β deposition in thecerebral cortex in Dementia with Lewy bodies is accompanied by arelative increase in AβPP mRNA isoforms containing the Kunitz proteaseinhibitor, Neurochemistry International, February, 2005, 46(3), p.253-260; Primavera J, and four others, Brain accumulation of amyloid-βin Non-Alzheimer Neurodegeneration, Jornal of Alzheimer's Disease,October, 1999, 1(3), p. 183-193), parkinsonism-dementia complex (see,for example, Schmidt M L, and six others, Amyloid plaques in Guamamyotrophic lateral sclerosis/parkinsonism-dementia complex containspecies of Aβ similar to those found in the amyloid plaques ofAlzheimer's disease and pathological aging, Acta Neuropathologica(Berl), February, 1998, 95(2), p. 117-122; Ito H, and three others,Demonstration of β amyloid protein-containing neurofibrillary tangles inparkinsonism-dementia complex on Guam, Neuropathology and appliedneurobiology, October, 1991, 17(5), p. 365-373), frontotemporal dementiaand parkinsonism linked to chromosome 17 (see, for example, Rosso S M,and three others, Coexistent tau and amyloid pathology in hereditaryfrontotemporal dementia with tau mutations, Annals of the New Yorkacademy of sciences, 2000, 920, p. 115-119), argyrophilic grain dementia(see, for example, Tolnay M, and four others, Low amyloid(Aβ) plaqueload and relative predominance of diffuse plaques distinguishargyrophilic grain disease from Alzheimer's disease, Neuropathology andapplied neurobiology, August, 1999, 25(4), p. 295-305), Niemann-Pickdisease (see, for example, Jin L W, and three others, Intracellularaccumulation of amyloidogenic fragments of amyloid-β precursor proteinin neurons with Niemann-Pick type C defects is associated with endosomalabnormalities, American Journal of Pathology, March, 2004, 164(3), p.975-985), amyotrophic lateral sclerosis (see, for example, Sasaki S, andone other, Immunoreactivity of β-amyloid precursor protein inamyotrophic lateral sclerosis, Acta Neuropathologica (Berl), May, 1999,97(5), p. 463-468; Tamaoka A, and four others, Increased amyloid βprotein in the skin of patients with amyotrophic lateral sclerosis,Journal of neurology, August, 2000, 247(8), p. 633-635; Hamilton R L,and one other, Alzheimer disease pathology in amyotrophic lateralsclerosis, Acta Neuropathologica, June, 2004, 107(6), p. 515-522; TurnerB J, and six others, Brain β-amyloid accumulation in transgenic miceexpressing mutant superoxide dismutase 1, Neurochemical Research,December, 2004, 29(12), p. 2281-2286), hydrocephalus (see, for example,Weller R O, Pathology of cerebrospinal fluid and interstitial fluid ofthe CNS: Significance for Alzheimer disease, prion disorders andmultiple sclerosis, Journal of Neuropathology and ExperimentalNeurology, October, 1998, 57(10), p. 885-894; Silverberg G D, and fourothers, Alzheimer's disease, normal-pressure hydrocephalus, andsenescent changes in CSF circulatory physiology: a hypothesis, Lancetneurology, August, 2003, 2(8), p. 506-511; Weller R O, and three others,Cerebral amyloid angiopathy: Accumulation of Aβ in interstitial fluiddrainage pathways in Alzheimer's disease, Annals of the New York academyof sciences, April, 2000, 903, p. 110-117; Yow H Y, and one other, Arole for cerebrovascular disease in determining the pattern of β-amyloiddeposition in Alzheimer's disease, Neurology and applied neurobiology,2002, 28, p. 149; Weller R O, and four others, Cerebrovasculardisease isa major factor in the failure of elimination of Aβ from the aging humanbrain, Annals of the New York academy of sciences, November, 2002, 977,p. 162-168), paraparesis (see, for example, O'Riordan S, and sevenothers, Presenilin-1 mutation (E280G), spastic paraparesis, and cranialMRI white-matter abnormalities, Neurology, Oct. 8, 2002, 59(7), p.1108-1110; Matsubara-Tsutsui M, and seven others, Molecular evidence ofpresenilin 1 mutation in familial early onset dementia, American journalof Medical Genetics, Apr. 8, 2002, 114(3), p. 292-298; Smith M J, andeleven others, Variable phenotype of Alzheimer's disease with spasticparaparesis, Annals of Neurology, 2001, 49(1), p. 125-129; Crook R, andseventeen others, A variant of Alzheimer's disease with spasticpararesis and unusual plaques due to deletion of exon 9 of presenilin 1,Nature Medicine, April, 1998; 4(4), p. 452-455), progressivesupranuclear palsy (see, for example, Barrachina M, and six others,Amyloid-β deposition in the cerebral cortex in Dementia with Lewy bodiesis accompanied by a relative increase in AβPP mRNA isoforms containingthe Kunitz protease inhibitor, Neurochemistry International, February,2005, 46(3), p. 253-260; Primavera J, and four others, Brainaccumulation of amyloid-β in Non-Alzheimer Neurodegeneration, Jornal ofAlzheimer's Disease, October, 1999, 1(3), p. 183-193), intracerebralhemorrhage (see, for example, Atwood C S, and three others,Cerebrovascular requirement for sealant, anti-coagulant and remodelingmolecules that allow for the maintenance of vascular integrity and bloodsupply, Brain Research Reviews, September, 2003, 43(1), p. 164-78;Lowenson J D, and two others, Protein aging: Extracellular amyloidformation and intracellular repair, Trends in cardiovascular medicine,1994, 4(1), p. 3-8), convulsion (see, for example, Singleton A B, andthirteen others, Pathology of early-onset Alzheimer's disease casesbearing the Thr113-114ins presenilin-1 mutation, Brain, December, 2000,123(Pt12), p. 2467-2474), mild cognitive impairment (see, for example,Gattaz W F, and four others, Platelet phospholipase A2 activity inAlzheimer's disease and mild cognitive impairment, Journal of NeuralTransmission, 2004, May, 111(5), p. 591-601; Assini A, and fourteenothers, Plasma levels of amyloid β-protein 42 are increased in womenwith mild cognitive impariment, Neurology, Sep. 14, 2004, 63(5), p.828-831), arteriosclerosis (see, for example, De Meyer G R, and eightothers, Platelet phagocytosis and processing of β-amyloid precursorprotein as a mechanism of macrophage activation in atherosclerosis,Circulation Research, Jun. 14, 2002, 90(11), p. 1197-1204).

The “5-membered aromatic heterocyclic group”, “6- to 14-memberedaromatic hydrocarbon ring group”, “5- to 14-membered aromaticheterocyclic group”, “6- to 14-membered non-aromatic hydrocarbon ringgroup” and “5- to 14-membered non-aromatic heterocyclic group” in thecompound represented by the formula (I) of the present invention whichis effective for treatment or prevention of a disease caused by Aβ aredefined as follows.

The “5-membered aromatic heterocyclic group” is a 5-membered aromaticheterocyclic group containing one or more hetero atoms selected from thegroup consisting of a nitrogen atom, a sulfur atom and an oxygen atomsuch as:

The “6- to 14-membered aromatic hydrocarbon ring group” refers to amonocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having6 to 14 carbon atoms. Preferable examples of the group include 6- to14-membered monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ringgroups such as a phenyl group, an indenyl group, a naphthyl group, anazulenyl group, a heptalenyl group, a biphenyl group, a fluorenyl group,a phenalenyl group, a phenanthrenyl group and an anthracenyl group.

The “5- to 14-membered aromatic heterocyclic group” refers to amonocyclic, bicyclic or tricyclic aromatic heterocyclic group having 5to 14 carbon atoms. Preferable examples of the group include (1)nitrogen-containing aromatic heterocyclic groups such as a pyrrolylgroup, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, apyrazinyl group, a pyrazolinyl group, an imidazolyl group, an indolylgroup, an isoindolyl group, an indolizinyl group, a purinyl group, anindazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinylgroup, a phthalazinyl group, a naphthyridinyl group, a quinoxalinylgroup, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, animidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group,a phenanthridinyl group, a carbazolyl group, a perimidinyl group, aphenanthrolinyl group and a phenacyl group, (2) sulfur-containingaromatic heterocyclic groups such as a thienyl group and a benzothienylgroup, (3) oxygen-containing aromatic heterocyclic groups such as afuryl group, a pyranyl group, a cyclopentapyranyl group, a benzofuranylgroup and an isobenzofuranyl group and (4) aromatic heterocyclic groupscontaining two or more hetero atoms selected from the group consistingof a nitrogen atom, a sulfur atom and an oxygen atom such as a thiazolylgroup, an isothiazolyl group, a benzothiazolinyl group, abenzothiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, afurazanyl group, a phenoxazinyl group, a pyrazoloxazolyl group, animidazothiazolyl group, a thienofuryl group, a furopyrrolyl group and apyridooxazinyl group.

The “6- to 14-membered non-aromatic hydrocarbon ring group” refers to acyclic aliphatic hydrocarbon group having 6 to 14 carbon atoms. Examplesof the group include cyclic aliphatic hydrocarbon groups having 6 to 14carbon atoms such as a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctylgroup, a spiro[3.4]octanyl group, a decanyl group, an indanyl group, a1-acenaphthenyl group, a cyclopentacyclooctenyl group, abenzocyclooctenyl group, an indenyl group, a tetrahydronaphthyl group, a6,7,8,9-tetrahydro-5H-benzocycloheptenyl group and a1,4-dihydronaphthalenyl group.

The “5- to 14-membered non-aromatic heterocyclic group” 1) has 5 to 14ring-forming atoms, 2) contains 1 to 5 hetero atoms such as a nitrogenatom, —O— or —S— in the ring-forming atoms, and 3) may contain one ormore carbonyl groups, double bonds or triple bonds in the ring, andrefers not only to a 5- to 14-membered non-aromatic monocyclicheterocyclic group but also to a saturated heterocyclic group condensedwith an aromatic hydrocarbon ring group or a saturated hydrocarbon ringgroup or saturated heterocyclic group condensed with an aromaticheterocyclic group. Specific examples of the 5- to 14-memberednon-aromatic heterocyclic group include an azetidinyl ring, apyrrolidinyl ring, a piperidinyl ring, an azepanyl ring, an azocanylring, a tetrahydrofuranyl ring, a tetrahydropyranyl ring, a morpholinylring, a thiomorpholinyl ring, a piperazinyl ring, a thiazolidinyl ring,a dioxanyl ring, an imidazolinyl ring, a thiazolinyl ring, a1,2-benzopyranyl ring, an isochromanyl ring, a chromanyl ring, anindolinyl ring, an isoindolinyl ring, an azaindanyl group, anazatetrahydronaphthyl group, an azachromanyl group, atetrahydrobenzofuranyl group, a tetrahydrobenzothienyl group, a2,3,4,5-tetrahydro-benzo[b]thienyl group, a3,4-dihydro-2H-benzo[b][1,4]dioxepinyl group, an indan-1-onyl group, a6,7-dihydro-5H-cyclopentapyrazinyl group, a 6,7-dihydro-5H-[1]pyridinylgroup, a 6,7-dihydro-5H-[1]pyridinyl group, a5,6-dihydro-4H-cyclopenta[b]thienyl group, a4,5,6,7-tetrahydro-benzo[b]thienyl group, a3,4-dihydro-2H-naphthale-1-onyl group, a 2,3-dihydro-isoindol-1-onylgroup, a 3,4-dihydro-2H-isoquinolin-1-onyl group and a3,4-dihydro-2H-benzo[1,4]oxapinyl group.

Substituent groups A1 and A2 refer to the following groups.

Substituent Group A1 refers to (1) a hydrogen atom, (2) a halogen atom,(3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8cycloalkyl group which may be substituted with 1 to 3 substituentsselected from Substituent Group A2, (7) a C2-6 alkenyl group which maybe substituted with 1 to 3 substituents selected from Substituent GroupA2, (8) a C2-6 alkynyl group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (9) a C3-8 cycloalkoxygroup, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) aC1-6 alkylcarbonyl group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (13) a C1-6 alkylthiogroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (14) a C1-6 alkylsulfinyl group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(15) a C1-6 alkylsulfonyl group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (16) a hydroxyiminogroup, (17) a C1-6 alkoxyimino group, (18) a C1-6 alkyl group which maybe substituted with 1 to 3 substituents selected from Substituent GroupA2, (19) a C1-6 alkoxy group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (20) an amino groupwhich may be substituted with 1 or 2 substituents selected fromSubstituent Group A2, (21) a carbamoyl group which may be substitutedwith 1 or 2 substituents selected from Substituent Group A2, (22) a 6-to 14-membered aromatic hydrocarbon ring group which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (23) a 5-to 14-membered aromatic heterocyclic group which may be substituted with1 to 3 substituents selected from Substituent Group A2, (24) a 6- to14-membered non-aromatic hydrocarbon ring group which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (25) a 5-to 14-membered non-aromatic heterocyclic group which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (26) a C2-6alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30)—X-A (wherein X represents an imino group, —O— or —S— and A represents a6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-memberedaromatic heterocyclic group which may be substituted with 1 to 3substituents selected from Substituent Group A2), (31) —CO-A (wherein Ais as defined above), (32) ═CH-A (wherein A is as defined above), (33) acarboxyl group, (34) a C1-6 alkoxycarbonyl group or (35) an azido group.

Substituent Group A2 refers to (1) a hydrogen atom, (2) a halogen atom,(3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group,(9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) aformyl group, (12) a C1-6 alkylcarbonyl group, (13) a C1-6 alkylthiogroup, (14) a C1-6 alkylsulfinyl group, (15) a C1-6 alkylsulfonyl group,(16) a hydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (19) a C1-6 alkoxy group(wherein the C1-6 alkoxy group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (20) an amino group which may besubstituted with 1 or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups,(21) a carbamoyl group which may be substituted with 1 or 2 C1-6 alkylgroups, (22) a 6- to 14-membered aromatic hydrocarbon ring group, (23) a5- to 14-membered aromatic heterocyclic group, (24) a 6- to 14-memberednon-aromatic hydrocarbon ring group, (25) a 5- to 14-memberednon-aromatic heterocyclic group, (26) a C2-6 alkenyloxy group, (27) aC2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8cycloalkylsulfonyl group, (30) —X-A′ (wherein X represents an iminogroup, —O—, —S— or —SO₂— and A′ represents a 6- to 14-membered aromatichydrocarbon ring group or a 5- to 14-membered aromatic heterocyclicgroup which may be substituted with 1 to 3 halogen atoms), (31) —CO-A′(wherein A′ is as defined above) or (32) ═CH-A′ (wherein A′ is asdefined above).

The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromineatom, an iodine atom or the like and is preferably a fluorine atom, achlorine atom or a bromine atom.

The “C3-8 cycloalkyl group” refers to a cyclic alkyl group having 3 to 8carbon atoms. Preferable examples of the group include a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, acycloheptyl group and a cyclooctyl group.

The “C2-6 alkenyl group” refers to an alkenyl group having 2 to 6 carbonatoms. Preferable examples of the group include linear or branchedalkenyl groups such as a vinyl group, an allyl group, a 1-propenylgroup, an isopropenyl group, a 1-buten-1-yl group, a 1-buten-2-yl group,a 1-buten-3-yl group, a 2-buten-1-yl group and a 2-buten-2-yl group.

The “C2-6 alkynyl group” refers to an alkynyl group having 2 to 6 carbonatoms. Preferable examples of the group include linear or branchedalkynyl groups such as an ethynyl group, a 1-propynyl group, a2-propynyl group, a butynyl group, a pentynyl group and a hexynyl group.

The “C3-8 cycloalkoxy group” refers to a cyclic alkyl group having 3 to8 carbon atoms in which one hydrogen atom is replaced by an oxygen atom.Preferable examples of the group include a cyclopropoxy group, acyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, acycloheptyloxy group and a cyclooctyloxy group.

The “C3-8 cycloalkylthio group” refers to a cyclic alkyl group having 3to 8 carbon atoms in which one hydrogen atom is replaced by a sulfuratom. Preferable examples of the group include a cyclopropylthio group,a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group,a cycloheptylthio group and a cyclooctylthio group.

The “C1-6 alkoxy group” refers to an alkyl group having 1 to 6 carbonatoms in which a hydrogen atom is replaced by an oxygen atom. Preferableexamples of the group include a methoxy group, an ethoxy group, ann-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxygroup, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, ani-pentoxy group, a sec-pentoxy group, a tert-pentoxy group, an n-hexoxygroup, an i-hexoxy group, a 1,2-dimethylpropoxy group, a 2-ethylpropoxygroup, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy group,a 1,1,2-trimethylpropoxy group, a 1,1,2-trimethylpropoxy group, a1,1-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2-ethylbutoxygroup, a 1,3-dimethylbutoxy group, a 2-methylpentoxy group, a3-methylpentoxy group and a hexyloxy group.

The “C1-6 alkylthio group” refers to an alkyl group having 1 to 6 carbonatoms in which one hydrogen atom is replaced by a sulfur atom.Preferable examples of the group include a methylthio group, anethylthio group, an n-propylthio group, an i-propylthio group, ann-butylthio group, an i-butylthio group, a tert-butylthio group, ann-pentylthio group, an i-pentylthio group, a neopentylthio group, ann-hexylthio group and a 1-methylpropylthio group.

The “C1-6 alkylcarbonyl group” refers to an alkyl group having 1 to 6carbon atoms in which one hydrogen atom is replaced by a carbonyl group.Preferable examples of the group include an acetyl group, a propionylgroup and a butyryl group.

The “C1-6 alkylsulfinyl group” refers to an alkyl group having 1 to 6carbon atoms in which one hydrogen atom is substituted with a sulfinylgroup. Preferable examples of the group include a methylsulfinyl group,an ethylmethylsulfinyl group, an n-propylsulfinyl group, ani-propylsulfinyl group, an n-butylsulfinyl group, an i-butylsulfinylgroup, a tert-butylsulfinyl group, an n-pentylsulfinyl group, ani-pentylsulfinyl group, a neopentylsulfinyl group, an n-hexylsulfinylgroup and a 1-methylpropylsulfinyl group.

The “C1-6 alkylsulfonyl group” refers to an alkyl group having 1 to 6carbon atoms in which one hydrogen atom is replaced by a sulfonyl group.Preferable examples of the group include a methanesulfonyl group and anethanesulfonyl group.

The “C1-6 alkoxyimino group” refers to an imino group in which ahydrogen atom is replaced by a C1-6 alkoxy group. Preferable examples ofthe group include a methoxyimino group and an ethoxyimino group.

The “C1-6 alkyl group” refers to an alkyl group having 1 to 6 carbonatoms. Preferable examples of the group include linear or branched alkylgroups such as a methyl group, an ethyl group, an n-propyl group, ani-propyl group, an n-butyl group, an i-butyl group, a tert-butyl group,an n-pentyl group, an i-pentyl group, a neopentyl group, an n-hexylgroup, a 1-methylpropyl group, an 1,2-dimethylpropyl group, a1-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a1-methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylbutyl group, a2,2-dimethylbutyl group, a 2-ethylbutyl group, a 1,3-dimethylbutylgroup, a 2-methylpentyl group and a 3-methylpentyl group.

The “C2-6 alkenyloxy group” refers to an alkenyl group having 2 to 6carbon atoms in which one hydrogen atom is replaced by an oxygen atom.Preferable examples of the group include linear or branched alkenyloxygroups such as a vinyloxy group, an allyloxy group, a 1-propenyloxygroup, an isopropenyloxy group, a 1-buten-1-yloxy group, a1-buten-2-yloxy group, a 1-buten-3-yloxy group, a 2-buten-1-yloxy groupand a 2-buten-2-yloxy group.

The “C2-6 alkynyloxy group” refers to an alkynyl group having 2 to 6carbon atoms in which one hydrogen atom is replaced by an oxygen atom.Preferable examples of the group include linear or branched alkynyloxygroups such as an ethynyloxy group, a 1-propynyloxy group, a2-propynyloxy group, a butynyloxy group, a pentynyloxy group and ahexynyloxy group.

The “C3-8 cycloalkylsulfonyl group” refers to a cyclic alkyl grouphaving 3 to 8 carbon atoms in which one hydrogen atom is replaced by asulfonyl group. Preferable examples of the group include acyclopropylsulfonyl group, a cyclobutylsulfonyl group, acyclopentylsulfonyl group, a cyclohexylsulfonyl group, acycloheptylsulfonyl group and a cyclooctylsulfonyl group.

The “C3-8 cycloalkylsulfinyl group” refers to a cyclic alkyl grouphaving 3 to 8 carbon atoms in which one hydrogen atom is replaced by asulfinyl group. Preferable examples of the group include acyclopropylsulfinyl group, a cyclobutylsulfinyl group, acyclopentylsulfinyl group, a cyclohexylsulfinyl group, acycloheptylsulfinyl group and a cyclooctylsulfinyl group.

The “C1-6 alkoxycarbonyl group” refers to a carbonyl group in which ahydrogen atom is substituted with a C1-6 alkyl group. Preferableexamples of the group include an ethoxycarbonyl group.

Examples of the pyridinyl group as Ar₂ which may be substituted with ahydroxyl group include a tautomer represented by the following formula:

Examples of the “Het which is a group represented by the followingformula”:

wherein R³ and R⁴ are the same or different and each represent asubstituent selected from Substituent Group A1, or R³ and R⁴ are takentogether with a carbon atom to which they are bonded to form ═CH-A(wherein A represents a 6- to 14-membered aromatic hydrocarbon ringgroup or a 5- to 14-membered aromatic heterocyclic group which may besubstituted with 1 to 3 substituents selected from Substituent GroupA2), X₂ represents a methylene group or an oxygen atom and n_(a)represents an integer of 0 to 2, include groups represented by theformulas:

wherein R³ and R⁴ are the same or different and each represent asubstituent selected from Substituent Group A1, or R³ and R⁴ are takentogether with a carbon atom to which they are bonded to form ═CH-A(wherein A represents a 6- to 14-membered aromatic hydrocarbon ringgroup or a 5- to 14-membered aromatic heterocyclic group which may besubstituted with 1 to 3 substituents selected from Substituent GroupA2).

Examples of the “Het represented by the following formula”:

wherein R³ and R⁴ are taken together with a carbon atom to which theyare bonded to form ═CH-A, include:

Examples of the “Het which is a group represented by the followingformula”:

wherein R⁵ and R⁶ are the same or different and each represent asubstituent selected from Substituent Group A1, X₃ represents amethylene group or an oxygen atom and n_(b) represents an integer of 0to 2, include:

wherein R⁵ and R⁶ are the same or different and each represent asubstituent selected from Substituent Group A1.

Examples of the “Het which is a group represented by the followingformula”:

wherein n_(c) represents an integer of 0 to 3, include:

Examples of the “Het which is a group represented by the followingformula”:

wherein n_(d) represents an integer of 0 to 3, include:

In the present invention, the “pharmacologically acceptable salt” is notparticularly limited insofar as it is a pharmacologically acceptablesalt formed with the compound of the general formula (I) which is aprophylactic or therapeutic agent for a disease caused by Aβ. Preferablespecific examples of the salt include hydrohalides (such ashydrofluorides, hydrochlorides, hydrobromides and hydroiodides),inorganic acid salts (such as sulfates, nitrates, perchlorates,phosphates, carbonates and bicarbonates), organic carboxylates (such asacetates, oxalates, maleates, tartrates, fumarates and citrates),organic sulfonates (such as methanesulfonates,trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates,toluenesulfonates and camphorsulfonates), amino acid salts (such asaspartates and glutamates), quaternary amine salts, alkali metal salts(such as sodium salts and potassium salts) and alkali earth metal salts(such as magnesium salts and calcium salts).

Next, the compound of the formula (I) of the present invention will bedescribed.

In the compound of the formula (I) or pharmacologically acceptable saltthereof, Ar₁ is preferably an imidazolyl group substituted with a C1-6alkyl group, and Ar₁ is more preferably an imidazolyl group substitutedwith a methyl group.

In the compound of the formula (I) or pharmacologically acceptable saltthereof, Ar₂ is preferably a pyridinyl group or a phenyl group which maybe substituted with a halogen atom, a hydroxyl group or a C1-6 alkoxygroup, Ar₂ is more preferably a phenyl group or a pyridinyl group,substituted with a C1-6 alkoxy group, Ar₂ is particularly preferably aphenyl group or a pyridinyl group, substituted with a methoxy group, andAr₂ is most preferably a pyridinyl group substituted with a methoxygroup.

In the compound of the formula (I) or pharmacologically acceptable saltthereof, X₁ is preferably —CR¹═CR²—, wherein R¹ and R² are the same ordifferent and each represent a hydrogen atom or a fluorine atom, and X₁is most preferably —CH═CH—.

In the compound of the formula (I) or pharmacologically acceptable saltthereof, Ar₁ and Ar more preferably have the following structuralformulas:

and most preferably have the following structural formulas:

In the compound of the formula (I) or pharmacologically acceptable saltthereof, Het is preferably a triazolyl group which may be substitutedwith 1 or 2 substituents selected from Substituent Group A1,

Het is preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein R³ and R⁴ are the same or different and each represent asubstituent selected from Substituent Group A1, or R³ and R⁴ are takentogether with a carbon atom to which they are bonded to form ═CH-A(wherein A represents a 6- to 14-membered aromatic hydrocarbon ringgroup or a 5- to 14-membered aromatic heterocyclic group which may besubstituted with 1 to 3 substituents selected from Substituent GroupA2), X₂ represents an oxygen atom or a methylene group which may besubstituted with a substituent selected from Substituent Group A1 andn_(a) represents an integer of 0 to 2,

Het is preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein R⁵ and R⁶ are the same or different and each represent asubstituent selected from Substituent Group A1, X₃ represents amethylene group which may be substituted with a substituent selectedfrom Substituent Group A1, or an oxygen atom and n_(b) represents aninteger of 0 to 2,

Het is preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein n_(c) represents an integer of 0 to 3, or

Het is preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein n_(d) represents an integer of 0 to 3,

Het is more preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein R³ and R⁴ are the same or different and each represent asubstituent selected from Substituent Group A1, or R³ and R⁴ are takentogether with a carbon atom to which they are bonded to form ═CH-A(wherein A represents a 6- to 14-membered aromatic hydrocarbon ringgroup or a 5- to 14-membered aromatic heterocyclic group which may besubstituted with 1 to 3 substituents selected from Substituent GroupA2), X₂ represents a methylene group which may be substituted with asubstituent selected from Substituent Group A1, or an oxygen atom andn_(a) represents an integer of 0 to 2, and

Het is more preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein n_(c) represents an integer of 0 to 3, and

Het is most preferably a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

Substituent Group A1 is preferably a group consisting of (1) a hydrogenatom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) anitro group, (6) a C3-8 cycloalkyl group which may be substituted with 1to 3 substituents selected from Substituent Group A2, (7) a C2-6 alkenylgroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (8) a C2-6 alkynyl group which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (9) a C3-8cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formylgroup, (12) a C1-6 alkylcarbonyl group which may be substituted with 1to 3 substituents selected from Substituent Group A2, (13) a C1-6alkylthio group which may be substituted with 1 to 3 substituentsselected from Substituent Group A2, (14) a C1-6 alkylsulfinyl groupwhich may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (15) a C1-6 alkylsulfonyl group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(16) a hydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6alkyl group which may be substituted with 1 to 3 substituents selectedfrom Substituent Group A2, (19) a C1-6 alkoxy group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(20) an amino group which may be substituted with 1 or 2 substituentsselected from Substituent Group A2, (21) a carbamoyl group which may besubstituted with 1 or 2 substituents selected from Substituent Group A2,(22) a 6- to 14-membered aromatic hydrocarbon ring group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(23) a 5- to 14-membered aromatic heterocyclic group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(24) a 6- to 14-membered non-aromatic hydrocarbon ring group which maybe substituted with 1 to 3 substituents selected from Substituent GroupA2, (25) a 5- to 14-membered non-aromatic heterocyclic group which maybe substituted with 1 to 3 substituents selected from Substituent GroupA2, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) aC3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group,(30) —X-A (wherein X represents an imino group, —O— or —S— and Arepresents a 6- to 14-membered aromatic hydrocarbon ring group or a 5-to 14-membered aromatic heterocyclic group which may be substituted with1 to 3 substituents selected from Substituent Group A2), (31) —CO-A(wherein A is as defined above), (32) ═CH-A (wherein A is as definedabove), (33) a carboxyl group, (34) a C1-6 alkoxycarbonyl group and (35)an azidoazido group.

Substituent Group A1 is more preferably a group consisting of (1) ahydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyanogroup, (5) a C3-8 cycloalkyl group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (6) a C1-6 alkyl groupwhich may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (7) a 6- to 14-membered aromatic hydrocarbon ringgroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (8) a 5- to 14-membered aromatic heterocyclicgroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (9) a 6- to 14-membered non-aromatic hydrocarbonring group which may be substituted with 1 to 3 substituents selectedfrom Substituent Group A2, (10) a 5- to 14-membered non-aromaticheterocyclic group which may be substituted with 1 to 3 substituentsselected from Substituent Group A2, (11) —X-A (wherein X represents animino group, —O— or —S— and A represents a 6- to 14-membered aromatichydrocarbon ring group or a 5- to 14-membered aromatic heterocyclicgroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2), (12) ═CH-A (wherein A represents a 6- to14-membered aromatic hydrocarbon ring group or a 5- to 14-memberedaromatic heterocyclic group which may be substituted with 1 to 3substituents selected from Substituent Group A2) and (13) an azidoazidogroup.

When Substituent Group A1 is a 6- to 14-membered aromatic hydrocarbonring group or a 5- to 14-membered aromatic heterocyclic group,Substituent Group A2 is preferably a group consisting of (1) a hydrogenatom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) anitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8)a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8cycloalkylthio group, (11) a formyl group, (12) a C1-6 alkylcarbonylgroup, (13) a C1-6 alkylthio group, (14) a C1-6 alkylsulfinyl group,(15) a C1-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a C1-6alkoxyimino group, (18) a C1-6 alkyl group (wherein the C1-6 alkyl groupmay be substituted with 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy group, aphenyl group which may be substituted with 1 to 3 halogen atoms and apyridinyl group which may be substituted with 1 to 3 halogen atoms),(19) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may besubstituted with 1 to 3 substituents selected from the group consistingof a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a phenyl groupwhich may be substituted with 1 to 3 halogen atoms and a pyridinyl groupwhich may be substituted with 1 to 3 halogen atoms), (20) an amino groupwhich may be substituted with 1 or 2 C1-6 alkyl groups or C1-6alkylcarbonyl groups, (21) a carbamoyl group which may be substitutedwith 1 or 2 C1-6 alkyl groups, (22) a 6- to 14-membered aromatichydrocarbon ring group, (23) a 5- to 14-membered aromatic heterocyclicgroup, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group,(25) a 5- to 14-membered non-aromatic heterocyclic group, (26) a C2-6alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30)—X-A′ (wherein X represents an imino group, —O—, —S— or —SO₂— and A′represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5-to 14-membered aromatic heterocyclic group which may be substituted with1 to 3 halogen atoms), (31) —CO-A′ (wherein A′ is as defined above) and(32) ═CH-A′ (wherein A′ is as defined above);

more preferably a group consisting of (1) a hydrogen atom, (2) a halogenatom, (3) a nitro group, (4) a C1-6 alkylcarbonyl group, (5) a C1-6alkylthio group, (6) a C1-6 alkyl sulfonyl group, (7) a C1-6 alkyl group(wherein the C1-6 alkyl group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (8) a C1-6 alkoxy group (whereinthe C1-6 alkoxy group may be substituted with 1 to 3 substituentsselected from the group consisting of a halogen atom, a hydroxyl group,a C1-6 alkoxy group, a phenyl group which may be substituted with 1 to 3halogen atoms and a pyridinyl group which may be substituted with 1 to 3halogen atoms), (9) an amino group which may be substituted with 1 or 2C1-6 alkyl groups or C1-6 alkylcarbonyl groups and (10) a 5- to14-membered aromatic heterocyclic group; and

most preferably a group consisting of (1) a hydrogen atom, (2) a halogenatom, (3) a C1-6 alkyl group (wherein the C1-6 alkyl group may besubstituted with 1 to 3 substituents selected from the group consistingof a halogen atom and a C1-6 alkoxy group) and (4) a C1-6 alkoxy group(wherein the C1-6 alkoxy group may be substituted with a halogen atom).

When Substituent Group A1 is a 6- to 14-membered non-aromatichydrocarbon ring group or a 5- to 14-membered non-aromatic heterocyclicgroup, Substituent Group A2 is preferably a group consisting of (1) ahydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyanogroup, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group,(10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a C1-6alkylcarbonyl group, (13) a C1-6 alkylthio group, (14) a C1-6alkylsulfinyl group, (15) a C1-6 alkylsulfonyl group, (16) ahydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6 alkylgroup (wherein the C1-6 alkyl group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (19) a C1-6 alkoxy group(wherein the C1-6 alkoxy group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (20) an amino group which may besubstituted with 1 or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups,(21) a carbamoyl group which may be substituted with 1 or 2 C1-6 alkylgroups, (22) a 6- to 14-membered aromatic hydrocarbon ring group, (23) a5- to 14-membered aromatic heterocyclic group, (24) a 6- to 14-memberednon-aromatic hydrocarbon ring group, (25) a 5- to 14-memberednon-aromatic heterocyclic group, (26) a C2-6 alkenyloxy group, (27) aC2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8cycloalkylsulfonyl group, (30) —X-A′ (wherein X represents an iminogroup, —O—, —S— or —SO₂— and A′ represents a 6- to 14-membered aromatichydrocarbon ring group or a 5- to 14-membered aromatic heterocyclicgroup which may be substituted with 1 to 3 halogen atoms), (31) —CO-A′(wherein A′ is as defined above) and (32) ═CH-A′ (wherein A′ is asdefined above); and

more preferably a group consisting of (1) a hydrogen atom, (2) a C1-6alkylcarbonyl group, (3) a C1-6 alkyl group (wherein the C1-6 alkylgroup may be substituted with 1 to 3 substituents selected from thegroup consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxygroup, a phenyl group which may be substituted with 1 to 3 halogen atomsand a pyridinyl group which may be substituted with 1 to 3 halogenatoms), (4) a 6- to 14-membered aromatic hydrocarbon ring group, (5)—X-A′ (wherein X represents an imino group, —O—, —S— or —SO₂— and A′represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5-to 14-membered aromatic heterocyclic group which may be substituted with1 to 3 halogen atoms) and (6) —CO-A′ (wherein A′ is as defined above).

The compound or pharmacologically acceptable salt, wherein the compoundis at least one selected from the following group, for example, isparticularly suitable and useful as a therapeutic or prophylactic agentfor a disease caused by amyloid-β such as Alzheimer's disease, seniledementia, Down's syndrome or amyloidosis.

-   1)    (−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   2)    (−)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   3)    (−)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   4)    (−)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol,-   5)    (−)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,-   6)    8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   7)    8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   8)    (−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole,-   9)    (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[1,5-a]pyridine,-   10)    (−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   11)    (−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   12)    (−)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   13)    (+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   14)    (+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   15)    (−)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   16)    (−)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   17)    (+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,-   18)    (−)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   19)    (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   20)    (+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   21)    (−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   22)    (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   23)    (+)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   24)    (−)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   25)    (+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   26)    (−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile,-   27)    (−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine,-   28)    (−)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   29)    (−)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   30)    (−)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   31)    (−)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   32)    (−)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   33)    (−)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine    and-   34)    (−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   35)    (−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   36)    (−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,-   37)    (−)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   38)    (5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,-   39)    (S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,    and-   40)    (S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole.

Methods for preparing the compound of the general formula (I) of thepresent invention will be described below.

The compound represented by the general formula (I):

wherein Ar₁, Ar₂, X₁ and Het are as defined above, is synthesizedaccording to a method such as the following General Preparation Method 1to General Preparation Method 8, for example. It is obvious that, inorder to prepare the compound of the present invention conveniently, themethod comprises a protection reaction step and a deprotection reactionstep appropriately, using a protecting group known to a person skilledin the art which is suitably selected for each step (see T. Greene etal., “Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc.,New York, 1981). It is also obvious that, in order to prepare thecompound of the present invention conveniently, all isomers and isomermixtures such as geometric isomers which can be generated from thestructure of the compound, optical isomers based on asymmetric carbon,stereoisomers, and tautomers can be prepared as a single compound by atechnique known to a person skilled in the art which is suitable foreach step such as fractional crystallization or column chromatography.[General Preparation Method 1]

Typically used General Preparation Method 1 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-3, III-4,III-6, III-7 or III-8):

is a partial structure corresponding to the above-described Het, whereinAr₁, Ar₂ and X₁ are as defined above; X₅, X₆, Y₁₀ and Y₁₁ are the sameor different and each represent a carbon atom, a nitrogen atom or asulfur atom; R¹⁰, R¹¹ and R¹² are the same or different and representgroups selected from the above Substituent Group A1 which may optionallyform a ring; L₁ represents a halogen atom such as a chlorine atom, abromine atom or an iodine atom, a sulfonate group such as amethanesulfonate group, a p-toluenesulfonate group or atrifluoromethanesulfonate group, or a hydroxyl group; L₂ represents ahalogen atom such as a chlorine atom, a bromine atom or an iodine atom,a sulfonate group such as a methanesulfonate group, a p-toluenesulfonategroup or a trifluoromethanesulfonate group, a boronic acid group or aboronate group such as a boronic acid pinacol ester group; X₄ representsa carbon atom or an oxygen atom; nd, ne, ni and nj each represent aninteger of 1 to 2; and nl represents an integer of 0 to 2.

The above General Preparation Method 1 includes a method of condensing acarboxylic acid compound (1) with a compound (2a) in Step 1-1 to convertthe carboxylic acid compound (1) into an ester compound (3) and reactingthe ester compound (3) with ammonia, an ammonium salt or formamide inStep 1-2 to prepare a compound of the general formula (I-9); a method ofreacting the compound of the general formula (I-9) with a compound (2b)in Step 1-3 to prepare a compound of the general formula (I-4); a methodof reacting the ester compound (3) with ammonia, an ammonium salt orformamide in Step 1-4 to convert the ester compound (3) into an oxazolecompound (21) and then reacting the oxazole compound (21) with an aminecompound (22) in Step 1-5 to prepare a compound of the general formula(I-4); a method of preparing a compound of the general formula (I-6) ora compound of the general formula (I-7) from the compound of the generalformula (I-9) in Step 1-6; a method of preparing a compound of thegeneral formula (I-6) or a compound of the general formula (I-7) fromthe oxazole compound (21) in Step 1-7; a method of preparing a compoundof the general formula (I-8) from the ester compound (3) and ammonia, anammonium salt or formamide in Step 1-8; and a method of preparing acompound of the general formula (I-8) from the oxazole compound (21) inStep 1-9.

[Preparation of Compound of General Formula (I-6) or Compound of GeneralFormula (I-7)]

The compound of the general formula (I-6) or the compound of the generalformula (I-7) can be prepared from a compound of the general formula(I-9) by intramolecular cyclization reaction according to Step 1-6.Specifically, Step 1-6 as an intramolecular cyclization reaction mayemploy a known method described in many documents such as N-alkylationreaction (see The Journal of Organic Chemistry, 1977, vol. 42, p. 3925,for example). The compound can also be prepared from an oxazole compound(21) by intramolecular cyclization reaction according to Step 1-7.Specifically, Step 1-7 may employ a method of forming a triazole orimidazole ring and cyclizing the second ring at the same time in thepresence or absence of a nitrogen atom source (see The Chemistry ofHeterocyclic Compounds. Imidazole and Derivatives, Part I, p. 33,Inters. Publish. 1953, for example).

Step 1-6 is preferably, for example, a method of stirring a compound ofthe general formula (I-9), wherein X₁ is —CR¹═CR²¹— and R²¹ represents aC1-6 alkyl group substituted with a halogen atom or a C1-6 alkoxy groupsubstituted with a halogen atom, or R¹¹ represents a C1-6 alkyl group(wherein the C1-6 alkyl group is substituted with a halogen atom, a C1-6alkoxy group substituted with a halogen atom or a C1-6 alkylamino groupsubstituted with a halogen atom), in a solvent in the presence of 1.0 to10.0 equivalents of a base with respect to the compound of the generalformula (I-9). The base used varies according to the starting materialand is not particularly limited. Preferable examples of the base includealkali metal hydrides (such as sodium hydride and lithium hydride),alkali metal salts (such as potassium carbonate, sodium carbonate andcesium carbonate), metal alkoxides (such as sodium methoxide andtert-butyl potassium) and organometallic salts (such as lithiumdiisopropyl amide and lithium hexamethyldisilazane). The solvent usedvaries according to the starting material, and is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent include ether solvents such astetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solventssuch as methylene chloride, 1,2-dichloroethane and chloroform; polarsolvents such as N,N-dimethylformamide and N-methylpyrrolidone; nonpolarsolvents such as toluene and benzene; and a mixture thereof. Thereaction temperature must be a temperature that can complete thereaction without promoting formation of an undesirable by-product, andis preferably −78° C. to 200° C., for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization.

Step 1-7 is preferably, for example, a method of stirring an oxazolecompound (21), wherein X₁ is —CR¹═CR²¹— and R²¹ represents a C1-6 alkylgroup substituted with a halogen atom or a C1-6 alkoxy group substitutedwith a halogen atom, or R¹¹ represents a C1-6 alkyl group (wherein theC1-6 alkyl group is substituted with a halogen atom, a C1-6 alkoxy groupsubstituted with a halogen atom or a C1-6 alkylamino group substitutedwith a halogen atom), in a solvent in the presence of 1.0 to 100equivalents of ammonia or an ammonium salt such as ammonium acetate withrespect to the oxazole compound (21). Step 1-7 may also be a method ofstirring an oxazole compound (21), wherein X₁ is —CR¹═CR²¹— and R²¹represents a C1-6 alkyl group substituted with an amino group or a C1-6alkoxy group substituted with an amino group, or R¹¹ represents a C1-6alkyl group (wherein the C1-6 alkyl group is substituted with an aminogroup, a C1-6 alkoxy group substituted with an amino group or a C1-6alkylamino group substituted with an amino group), in a solvent. Thesolvent used is not particularly limited insofar as the solvent does notinhibit the reaction and allows the starting material to be dissolvedtherein to a certain extent. Preferable examples of the solvent includenonpolar solvents such as toluene and benzene; alcohol solvents such asmethanol and ethanol; organic acids such as acetic acid; water; and amixture thereof. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 250° C., for example.Under preferable reaction conditions, the reaction is completed in 1 to24 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

[Preparation of Compound of General Formula (I-8)]

The compound of the general formula (I-8) can be prepared from an estercompound (3) according to Step 1-8 using ammonia, an ammonium salt orformamide as a nitrogen source, for example. The compound can also beprepared from an oxazole compound (21) according to Step 1-9 usingammonia, an ammonium salt or formamide as a nitrogen source, forexample. Specifically, Step 1-8 or Step 1-9 varies according to thestarting material and is not particularly limited insofar as theconditions are similar to those in this reaction. A known methoddescribed in many documents may be used for the reaction (see TheChemistry of Heterocyclic Compounds. Imidazole and Derivatives, Part I,p. 33, Inters. Publish. 1953, for example). The reaction is preferably amethod of stirring an ester compound (3) or an oxazole compound (21) and1.0 to 100.0 equivalents of ammonia or an ammonium salt such as ammoniumacetate with respect to the ester compound (3) or the oxazole compound(21) in a solvent, for example. The solvent used is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent include nonpolar solvents such astoluene and benzene; alcohol solvents such as methanol and ethanol;organic acids such as acetic acid; water; and a mixture thereof.Formamide may optionally be used as a nitrogen atom source and asolvent. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 250° C., for example.The yield may be improved when the reaction is performed using a tightcontainer. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

[Preparation of Compound of General Formula (I-4)]

The compound of the general formula (I-4) can be prepared by reacting acompound of the general formula (I-9) with a compound of the generalformula (2b) according to Step 1-3. Specifically, Step 1-3 may employ aknown method described in many documents such as N-alkylation reaction(see The Journal of Organic Chemistry, 1977, vol. 42, p. 3925, forexample) or N-arylation reaction (see The Journal of Organic Chemistry,2001, vol. 66, p. 7892; Journal of Medicinal Chemistry, 1981, vol. 24,p. 1139; or Journal of Medicinal Chemistry, 1991, vol. 39, p. 2671, forexample).

N-alkylation reaction is preferably, for example, a method of stirring acompound of the general formula (I-9) and 1.0 to 10.0 equivalents of acompound (2b), wherein L₂ represents a halogen atom such as a chlorineatom, a bromine atom or an iodine atom or a sulfonate group such as amethanesulfonate group, a p-toluenesulfonate group or atrifluoromethanesulfonate group, with respect to the compound of thegeneral formula (I-9) in a solvent in the presence of 1.0 to 10.0equivalents of a base with respect to the compound of the generalformula (I-9). The base used varies according to the starting materialand is not particularly limited. Preferable examples of the base includealkali metal hydrides (such as sodium hydride and lithium hydride),alkali metal salts (such as potassium carbonate, sodium carbonate andcesium carbonate) and metal alkoxides (such as sodium methoxide andpotassium tert-butoxide). The solvent used varies according to thestarting material, and is not particularly limited insofar as thesolvent does not inhibit the reaction and allows the starting materialto be dissolved therein to a certain extent. Preferable examples of thesolvent include ether solvents such as tetrahydrofuran, 1,4-dioxane anddiethyl ether; halogenated solvents such as methylene chloride,1,2-dichloroethane and chloroform; polar solvents such asN,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents such astoluene and benzene; and a mixture thereof. The reaction temperaturemust be a temperature that can complete the reaction without promotingformation of an undesirable by-product, and is preferably 0° C. to 200°C., for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

N-arylation reaction may be i) Ullmann reaction, ii) a coupling reactionof an arylboronic acid derivative using a copper compound or iii)nucleophilic substitution reaction.

In the case of i) Ullmann reaction, there are no specific limitations tothe reaction conditions. Ullmann reaction is preferably, for example, amethod of stirring a compound of the general formula (I-9) and 1.0 to10.0 equivalents of a compound (2b), wherein L₂ represents a halogenatom such as a chlorine atom, a bromine atom or an iodine atom, withrespect to the compound of the general formula (I-9) in a solvent in thepresence of 0.01 to 1.0 equivalent of a copper reagent such as copper,copper bromide or copper iodide with respect to the compound of thegeneral formula (I-9) with 1.0 to 10.0 equivalents of a base added withrespect to the compound of the general formula (I-9). The base usedvaries according to the starting material and is not particularlylimited. Preferable examples of the base include alkali metal salts(such as potassium carbonate, sodium carbonate, potassium acetate,sodium acetate and cesium carbonate) and metal alkoxides (such as sodiummethoxide and potassium tert-butoxide). The solvent used variesaccording to the starting material, the reagent and the like, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include ethersolvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as amyl alcohol and isopropyl alcohol;polar solvents such as N,N-dimethylformamide and N-methylpyrrolidone;nonpolar solvents such as toluene, benzene and dichlorobenzene; and amixture thereof. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 200° C., for example.Under preferable reaction conditions, the reaction is completed in 1 to24 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

The ii) coupling reaction of an arylboronic acid derivative using acopper compound is preferably, for example, a method of stirring acompound of the general formula (I-9) and 1.0 to 10.0 equivalents of acompound (2b), wherein L₂ represents a boronic acid group or a boronategroup such as a boronic acid pinacol ester group, with respect to thecompound of the general formula (I-9) in a solvent in the presence of0.01 to 1.0 equivalent of a copper reagent such as copper, copperbromide or copper iodide with respect to the compound of the generalformula (I-9) with 1.0 to 10.0 equivalents of a base added with respectto the compound of the general formula (I-9). The base used variesaccording to the starting material, the solvent used and the like, andis not particularly limited insofar as the base does not inhibit thereaction. Preferable examples of the base include organic bases such astriethylamine, pyridine and tetramethylethylenediamine; alkali metalsalts such as potassium carbonate, sodium carbonate, potassium acetate,sodium acetate and cesium carbonate; and metal alkoxides such as sodiummethoxide and potassium tert-butoxide. The copper reagent used variesaccording to the starting material and is not particularly limited.Preferable examples of the copper reagent include copper acetate anddi-μ-hydroxo-bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)]chloride. The solvent used varies according to the startingmaterial, the reagent and the like, and is not particularly limitedinsofar as the solvent does not inhibit the reaction and allows thestarting material to be dissolved therein to a certain extent.Preferable examples of the solvent include ether solvents such astetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solventssuch as methylene chloride, 1,2-dichloroethane and chloroform; polarsolvents such as ethyl acetate, N,N-dimethylformamide andN-methylpyrrolidone; nonpolar solvents such as toluene, benzene anddichlorobenzene; and a mixture thereof. The reaction temperature must bea temperature that can complete the reaction without promoting formationof an undesirable by-product, and is preferably room temperature to 200°C., for example. Good results such as reduction in the reaction time andimprovement of the yield can be achieved when the reaction is performedin an oxygen atmosphere or air stream. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization.

In iii) nucleophilic substitution reaction, a compound of the generalformula (I-9) and 2.0 to 5.0 equivalents of a compound (2b), wherein L₂represents a halogen atom such as a chlorine atom, a bromine atom or aniodine atom or a sulfonate group such as a methanesulfonate group, ap-toluenesulfonate group or a trifluoromethanesulfonate group, withrespect to the compound of the general formula (I-9) are preferablystirred in a solvent in the presence or absence of 1.0 to 5.0equivalents of a base with respect to the compound of the generalformula (I-9), for example. The base used varies according to thestarting material and is not particularly limited. Preferable examplesof the base include sodium hydride, sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium carbonate, cesium carbonate,barium carbonate, pyridine, lutidine and triethylamine. The solvent usedvaries according to the starting material, and is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent include acetonitrile,tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide andN-methylpyrrolidine. The base may optionally be used as a solvent. Thereaction temperature must be a temperature that can complete thereaction without promoting formation of an undesirable by-product, andis preferably room temperature to 150° C., for example. Under preferablereaction conditions, the reaction is completed in 1 to 24 hours, and theprogress of the reaction can be monitored by a known chromatographytechnique. An undesirable by-product can be removed by a technique knownto a person skilled in the art such as a conventional chromatographytechnique or/and crystallization.

The compound of the general formula (I-4) can be prepared by reacting anoxazole compound (21) with an amine compound (22) according to Step 1-5.Specifically, Step 1-5 varies according to the starting material and isnot particularly limited insofar as the conditions are similar to thosein this reaction. A known method described in many documents may be usedfor the reaction (see Heterocyclic Compounds, vol. 5, Wiley, New York,N.Y. 1950, p. 214, for example). Preferably, an oxazole compound (21)and 1.0 to 100.0 equivalents of an amine compound (22) with respect tothe oxazole compound (21) are stirred in a solvent, for example. Thesolvent used is not particularly limited insofar as the solvent does notinhibit the reaction and allows the starting material to be dissolvedtherein to a certain extent. Preferable examples of the solvent includeether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as amyl alcohol and isopropyl alcohol;polar solvents such as N,N-dimethylformamide and N-methylpyrrolidone;nonpolar solvents such as toluene, benzene and dichlorobenzene; organicacids such as acetic acid; water; and a mixture thereof. The aminecompound (22) to be reacted may be used as a solvent. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferably roomtemperature to 200° C., for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization.

[Preparation of Compound of General Formula (I-9)]

The compound of the general formula (I-1) can be prepared from an estercompound (3) according to Step 1-2 using ammonia, an ammonium salt orformamide as a nitrogen atom source, for example. Specifically, Step 1-2varies according to the starting material and is not particularlylimited insofar as the conditions are similar to those in this reaction.A known method described in many documents may be used for the reaction(see The Chemistry of Heterocyclic Compounds. Imidazole and Derivatives,Part I, p. 33, Inters. Publish. 1953, for example). The reaction ispreferably a method of stirring an ester compound (3) and 1.0 to 100.0equivalents of ammonia or an ammonium salt such as ammonium acetate withrespect to the ester compound (3) in a solvent, for example. The solventused is not particularly limited insofar as the solvent does not inhibitthe reaction and allows the starting material to be dissolved therein toa certain extent. Preferable examples of the solvent include nonpolarsolvents such as toluene and benzene; alcohol solvents such as methanoland ethanol; organic acids such as acetic acid; water; and a mixturethereof. Formamide may optionally be used as a nitrogen atom source anda solvent. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 250° C., for example.The yield may be improved when the reaction is performed using a tightcontainer. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

[Preparation of Ester Compound (3)]

The ester compound (3) is prepared by condensation reaction of acarboxylic acid compound (1) with a compound (2a) according to Step 1-1.Specifically, Step 1-1 varies according to the starting material and isnot particularly limited insofar as the conditions are similar to thosein this reaction. A known method described in many documents may be usedfor the reaction. Preferable examples of the reaction include i)nucleophilic substitution reaction of a carboxylic acid compound (1)with a compound (2a), wherein L₁ represents a halogen atom such as achlorine atom, a bromine atom or an iodine atom or a sulfonate groupsuch as a methanesulfonate group, a p-toluenesulfonate group or atrifluoromethanesulfonate group (see Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol. 22, Yuki Gosei (OrganicSynthesis) [IV], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., November 1992, p. 49-50, for example) and ii) dehydrationcondensation reaction of a carboxylic acid compound (1) with a compound(2a) (see Shin Jikken Kagaku Koza (New Courses in ExperimentalChemistry), vol. 22, Yuki Gosei (Organic Synthesis) [IV], edited by TheChemical Society of Japan, Maruzen Co., Ltd., November 1992, p. 43-47,for example).

i) Nucleophilic substitution reaction is preferably, for example, amethod of stirring a carboxylic acid compound (1) and 1.0 to 10.0equivalents of a compound (2a) with respect to the carboxylic acidcompound (1) in a solvent in the presence of 1.0 to 10.0 equivalents ofa base with respect to the carboxylic acid compound (1). The base usedvaries according to the starting material and is not particularlylimited. Preferable examples of the base include alkali metal hydroxidessuch as sodium hydroxide and lithium hydroxide; alkali metal carbonatessuch as sodium carbonate; alkali metal salts of alcohols such as sodiummethoxide and potassium tert-butoxide; organic bases such astriethylamine, pyridine and diazabicyclononene; organic metals such asbutyl lithium and lithium diisobutylamide; alkali metal hydrides such assodium hydride; and alkali metal ammonium salts such as sodium amide.The solvent used varies according to the starting material and the baseused, and is not particularly limited insofar as the solvent does notinhibit the reaction and allows the starting material to be dissolvedtherein to a certain extent. Preferable examples of the solvent includepolar solvents such as nitromethane, acetonitrile,1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide;ether solvents such as tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane; nonpolar solvents such as benzene, toluene andxylene; alcohol solvents such as ethanol and methanol; halogenatedsolvents such as chloroform and methylene chloride; water; and a mixedsolvent thereof. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably −78 to 150° C., for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

ii) Dehydration condensation reaction is preferably, for example, amethod of stirring a carboxylic acid compound (1) and 1.0 to 10.0equivalents of a compound (2a) with respect to the carboxylic acidcompound (1) in a solvent in the presence of 0.1 to 10.0 equivalents ofa condensing agent with respect to the carboxylic acid compound (1). Thecondensing agent used varies according to the starting material and isnot particularly limited. Preferable examples of the condensing agentinclude inorganic acids such as hydrochloric acid and sulfuric acid;organic acids such as p-toluenesulfonic acid and methanesulfonic acid;and 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,diethyl cyanophosphonate, bis(2-oxo-3-oxazolidinyl)phosphonic chlorideand diphenylphosphoryl azide. Preferably, 1.0 to 5.0 equivalents ofN-hydroxysuccinimide, N-hydroxybenzotriazole or dimethylaminopyridinemay be added in order to make the reaction efficiently proceed, forexample. The solvent used varies according to the starting material andthe condensing agent used, and is not particularly limited insofar asthe solvent does not inhibit the reaction and allows the startingmaterial to be dissolved therein to a certain extent. Preferableexamples of the solvent include halogenated solvents such as chloroform,methylene chloride and 1,2-dichloroethane; polar solvents such astetrahydrofuran and N,N-dimethylformamide; and a mixed solvent thereof.The reaction temperature must be a temperature that can complete thereaction without promoting formation of an undesirable by-product, andis preferably ice-cold temperature to 150° C., for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique or/and crystallization.

[Preparation of Oxazole Compound (21)]

The oxazole compound (21) can be prepared by reacting an ester compound(3) with ammonia, an ammonium salt or formamide as a nitrogen atomsource according to Step 1-4, for example. Specifically, Step 1-4 variesaccording to the starting material and is not particularly limitedinsofar as the conditions are similar to those in this reaction. A knownmethod described in many documents may be used for the reaction (seeSynthesis, 1998, vol. 9, p. 1298, for example). Preferably, an estercompound (3) and 1.0 to 100.0 equivalents of ammonia or an ammonium saltsuch as ammonium acetate with respect to the ester compound (3) arestirred in a solvent, for example. The solvent used is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent include nonpolar solvents such astoluene and benzene; alcohol solvents such as methanol and ethanol;organic acids such as acetic acid; water; and a mixture thereof.Formamide may optionally be used as a nitrogen atom source and asolvent. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 250° C., for example.The yield may be improved when the reaction is performed using a tightcontainer. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

[Preparation of Compound (2b)]

The compound (2b) is commercially available or can be prepared by amethod known to a person skilled in the art (see Shin Jikken Kagaku Koza(New Courses in Experimental Chemistry), vol. 19, Yuki Gosei (OrganicSynthesis) [I], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., September 1992, p. 363-482; and Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol. 24, Yuki Gosei (OrganicSynthesis) [VI], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., June 1992, p. 61-90, for example).

[Preparation of Compound (22)]

The compound (22) is commercially available or can be prepared by amethod known to a person skilled in the art (see Shin Jikken Kagaku Koza(New Courses in Experimental Chemistry), vol. 20, Yuki Gosei (OrganicSynthesis) [II], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., July 1992, p. 279-372, for example).

[Preparation of Compound (2a)]

The compound (2a) is commercially available or can be prepared by amethod known to a person skilled in the art (see Shin Jikken Kagaku Koza(New Courses in Experimental Chemistry), vol. 19, Yuki Gosei (OrganicSynthesis) [I], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., September 1992, p. 363-482; and Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol. 20, Yuki Gosei (OrganicSynthesis) [II], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., July 1992, p. 1-110, for example).

[Preparation of Carboxylic Acid Compound (1)]

In the formula, Ar₁, Ar₂, R¹ and X₁ are as defined above; V₁ representsa protecting group for a carboxylic group such as a methyl group, anethyl group, a benzyl group, an allyl group, a triphenylmethyl group, atert-butyl group or a tert-butyldimethylsilyl group; L₃ and L₆ eachrepresent a hydrogen atom, a halogen atom such as a fluorine atom, achlorine atom, a bromine atom or an iodine atom, a sulfonate group suchas a trifluoromethanesulfonate group, a trialkyltin group or a leavinggroup such as a boronic acid or boronate group; L₄ represents a formylgroup, an alkanoyl group such as an acetyl group, an alkoxycarbonylgroup such as a methyl ester group, a halogen atom such as a fluorineatom, a chlorine atom, a bromine atom or an iodine atom, a sulfonategroup such as a trifluoromethanesulfonate group, a trialkyltin group ora boronic acid or boronate group; L₅ represents a halogen atom such as afluorine atom, a chlorine atom, a bromine atom or an iodine atom or asulfonate group such as a trifluoromethanesulfonate group; W representsa phosphate group such as a diethylphosphonyl group, adiphenylphosphonyl group or a bis(2,2,2-trifluoroethyl)phosphonyl group,a phosphonium salt such as triphenylphosphonium bromide or a silyl groupsuch as a trimethylsilyl group; R²⁶ is as defined for the R¹; R¹³ is asdefined for the R²; and R¹⁴ and R¹⁵ each represent a C1-6 alkyl group.

The carboxylic acid compound (1) is prepared by hydrolysis of an estercompound (8) according to Step 2-3. Specifically, Step 2-3 variesaccording to the starting material and is not particularly limitedinsofar as the conditions are similar to those in this reaction. A knownmethod described in many documents may be used for the reaction (seeShin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.22, Yuki Gosei (Organic Synthesis) [IV], edited by The Chemical Societyof Japan, Maruzen Co., Ltd., November 1992, p. 6-11, for example).Preferably, an ester compound (8) is stirred in a solvent in thepresence of 1.0 to 100.0 equivalents of a base or acid with respect tothe ester compound (8), for example. The base used varies according tothe starting material and is not particularly limited. Preferableexamples of the base include sodium hydride, sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium carbonate, cesium carbonate andbarium carbonate. The acid used varies according to the startingmaterial and is not particularly limited. Preferable examples of theacid include inorganic acids such as hydrochloric acid and sulfuricacid; organic acids such as trifluoroacetic acid and p-toluenesulfonicacid; and Lewis acids such as boron trichloride. The solvent used variesaccording to the starting material, and is not particularly limitedinsofar as the solvent does not inhibit the reaction and allows thestarting material to be dissolved therein to a certain extent.Preferable examples of the solvent include alcohol solvents such asmethanol, ethanol and ethylene glycol; ether solvents such astetrahydrofuran; halogenated solvents such as dichloromethane andchloroform; water; and a mixed solvent thereof. In the case of acidhydrolysis, an organic acid such as acetic acid or formic acid may beused as a solvent. The reaction temperature must be a temperature thatcan complete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 100° C., for example.Under preferable reaction conditions, the reaction is completed in 1 to24 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique or/and crystallization.

[Preparation of Ester Compound (8)]

The ester compound (8) can be prepared as shown by the above reactionformula, but the preparation is not limited thereto. Specifically, theester compound (8) can be prepared by reacting a compound (4) with acompound (5) in Step 2-1 to obtain a carbonyl compound (6) and thencondensing the carbonyl compound (6) by condensation reaction such asHorner-Emmons reaction, Wittig reaction or Peterson reaction in Step2-2, for example. Alternatively, the ester compound (8) can be preparedby subjecting a carbonyl compound (6) as a starting material to Step 2-4to prepare a compound (10) and condensing the compound (10) with acompound (11) by condensation reaction such as Horner-Emmons reaction,Wittig reaction or Peterson reaction in Step 2-5. Alternatively, theester compound (8) can be prepared by forming Ar₁ in a compound (17)from an amino compound (13) as a starting material through three-stagereaction in Step 2-7 and then performing coupling reaction of thecompound (17) with a compound (18a) or compound (18b) according to Step2-11. The ester compound (8) can also be prepared by converting acompound (15) as a starting material into a compound (17) according toStep 2-9 and then subjecting the compound (17) to Step 2-11.

[Conversion of Carbonyl Compound (6) into Ester Compound (8) andConversion of Compound (10) into Ester Compound (8)]

A carbonyl compound (6) can be converted into the ester compound (8) anda compound (10) can be converted into the ester compound (8) by a methodknown to a person skilled in the art. For example, the ester compound(8) can be prepared from a carbonyl compound (6) and a compound (7)according to Step 2-2. Alternatively, the ester compound (8) can beprepared from a compound (10) and a compound (11) according to Step 2-5.Specifically, coupling reaction in Step 2-2 or Step 2-5 varies accordingto the starting material and is not particularly limited insofar as theconditions are similar to those in this reaction. A method known to aperson skilled in the art may be used for the reaction. Preferableexamples of the method include Wittig reaction, Horner-Emmons reactionand Peterson reaction (see Shin Jikken Kagaku Koza (Courses inExperimental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis) [I],edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992,p. 57-85, for example).

In Wittig reaction, a compound (7) or compound (10), wherein Wrepresents a phosphonium salt, and 0.5 to 2.0 equivalents of a carbonylcompound (6) or a compound (11) with respect to the compound (7) orcompound (10) are preferably stirred in a solvent in the presence of 1.0to 5.0 equivalents of a base with respect to the compound (7) orcompound (10), for example. This reaction may be a method of firsttreating a compound (7) or compound (10) and a base to form a phosphorusylide and then adding a carbonyl compound (6) or a compound (11) to theylide; or a method of adding a base in the presence of a compound (7) orcompound (10) and a carbonyl compound (6) or a compound (11). Thisreaction is preferably performed in the presence of a solvent from theviewpoint of handleability and stirring efficiency. The solvent usedvaries according to the starting material and the base used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include polarsolvents such as nitromethane, acetonitrile, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solventssuch as benzene, toluene and xylene; alcohol solvents such as ethanoland methanol; halogenated solvents such as chloroform and methylenechloride; water; and a mixed solvent thereof. The base used variesaccording to the starting material and the solvent. Preferable examplesof the base include alkali metal hydroxides such as sodium hydroxide andlithium hydroxide; alkali metal carbonates such as sodium carbonate;alkali metal salts of alcohols such as sodium methoxide and potassiumtert-butoxide; organic bases such as triethylamine, pyridine anddiazabicyclononene; organic metals such as butyl lithium and lithiumdiisobutylamide; and alkali metal hydrides such as sodium hydride. Thereaction temperature must be a temperature that can complete thereaction without promoting formation of an undesirable by-product, andis preferably −78 to 150° C., for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization.

In Horner-Emmons reaction, a compound (7) or compound (10), wherein Wrepresents a phosphate group, and 0.5 to 2.0 equivalents of a carbonylcompound (6) or a compound (11) with respect to the compound (7) orcompound (10) are preferably stirred in a solvent in the presence of 1.0to 5.0 equivalents of a base with respect to the compound (7) orcompound (10), for example. This reaction may be a method of firsttreating a compound (7) or compound (10) and a base to form a carbanionand then adding a carbonyl compound (6) or a compound (11) to thecarbanion; or a method of adding a base in the presence of a compound(7) or compound (10) and a carbonyl compound (6) or a compound (11).This reaction is preferably performed in the presence of a solvent fromthe viewpoint of handleability and stirring efficiency. The solvent usedvaries according to the starting material and the base used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include polarsolvents such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide anddimethyl sulfoxide; ether solvents such as tetrahydrofuran, 1,4-dioxaneand 1,2-dimethoxyethane; nonpolar solvents such as benzene, toluene andxylene; alcohol solvents such as ethanol and methanol; water; and amixed solvent thereof. The base used varies according to the startingmaterial and the solvent. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; alkali metalhydrides such as sodium hydride; and alkali metal ammonium salts such assodium amide. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably −78 to 150° C., for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Peterson reaction, a compound (7) or compound (10), wherein Wrepresents a silyl group, and 0.5 to 2.0 equivalents of a carbonylcompound (6) or a compound (11) with respect to the compound (7) orcompound (10) are preferably stirred in a solvent in the presence of 1.0to 5.0 equivalents of a base with respect to the compound (7) orcompound (10), for example. This reaction may be a method of firsttreating a compound (7) or compound (10) and a base to form a carbanionand then adding a carbonyl compound (6) or a compound (11) to thecarbanion; or a method of adding a base in the presence of a compound(7) or compound (10) and a carbonyl compound (6) or a compound (11).This reaction is preferably performed in the presence of a solvent fromthe viewpoint of handleability and stirring efficiency. The solvent usedvaries according to the starting material and the base used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include polarsolvents such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide anddimethyl sulfoxide; ether solvents such as tetrahydrofuran, 1,4-dioxaneand 1,2-dimethoxyethane; nonpolar solvents such as benzene, toluene andxylene; alcohol solvents such as ethanol and methanol; water; and amixed solvent thereof. The base used varies according to the startingmaterial and the solvent. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; alkali metalhydrides such as sodium hydride; and alkali metal ammonium salts such assodium amide. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably −78 to 150° C., for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

[Conversion of Compound (17) into Ester Compound (8)]

A compound (17) can be converted into the ester compound (8) by a methodknown to a person skilled in the art. The ester compound (8) can beprepared from a compound (17) together with a compound (18a) or compound(18b) according to Step 2-11, for example. Specifically, the couplingreaction in Step 2-11 varies according to the starting material and isnot particularly limited insofar as the conditions are similar to thosein this reaction. A method known to a person skilled in the art may beused for the reaction. Preferable examples of the method includeMizoroki-Heck reaction (see R. F. Heck, “Org. Reactions.”, 1982, vol.27, p. 345, for example), Suzuki-Miyaura reaction (see A. Suzuki, “Chem.Rev.”, 1995, vol. 95, p. 2457, for example), Sonogashira reaction (seeK. Sonogashira, “Comprehensive Organic Synthesis”, 1991, vol. 3, p. 521)and Stille coupling reaction (see J. K. Stille, “Angew. Chem. Int. Ed.Engl.”, 1986, vol. 25, p. 508, for example).

In Mizoroki-Heck reaction, a halogen compound or triflate compound (17),wherein L₄ represents a chlorine atom, a bromine atom, an iodine atom ora sulfonate group such as a trifluoromethanesulfonate group, ispreferably coupled with 1.0 to 5.0 equivalents of an alkene compound(18a; wherein L₆ is a hydrogen atom) with respect to the compound (17)in the presence of 0.01 to 0.2 equivalent of a transition metal catalystwith respect to the compound (17), for example. This reaction ispreferably performed in the presence of a solvent from the viewpoint ofhandleability and stirring efficiency. The solvent used varies accordingto the starting material and the transition metal catalyst used, and isnot particularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere. The transition metal catalyst ispreferably a palladium complex, for example, and more preferably a knownpalladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). It is also preferable toappropriately add a phosphorus ligand (preferably triphenylphosphine,tri-o-tolylphosphine, tri-tert-butylphosphine or2-(di-tert-butylphosphino)biphenyl, for example) in order to make thereaction efficiently proceed. A preferable result may be achieved in thepresence of a base. The base used is not particularly limited insofar asthe base is used in a coupling reaction similar to this reaction.Preferable examples of the base include triethylamine,N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine andtetrabutylammonium chloride. Under preferable reaction conditions, thereaction is completed in 1 to 24 hours, and the progress of the reactioncan be monitored by a known chromatography technique.

In Suzuki-Miyaura reaction, a halogen compound ortrifluoromethanesulfonate compound (17), wherein L₄ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, is preferably coupled with 1.0 to5.0 equivalents of a boronic acid compound or boronate compound (18a;wherein L₆ is a boronic acid or boronate group) with respect to thecompound (17) in the presence of 0.01 to 0.5 equivalent of a transitionmetal catalyst with respect to the compound (17), for example. Thisreaction is preferably performed in the presence of a solvent from theviewpoint of handleability and stirring efficiency. The solvent usedvaries according to the starting material and the transition metalcatalyst used, and is not particularly limited insofar as the solventdoes not inhibit the reaction and allows the starting material to bedissolved therein to a certain extent. Preferable examples of thesolvent include acetonitrile, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone,N,N-dimethylformamide, water and a mixed solvent thereof. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 200° C. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere. Under preferable reaction conditions,the reaction is completed in 1 to 24 hours, and the progress of thereaction can be monitored by a known chromatography technique. Thetransition metal catalyst is preferably a known palladium complex, andmore preferably a known palladium complex such as palladium (II)acetate, dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0), ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand(preferably triphenylphosphine, tri-o-tolylphosphine,tricyclohexylphosphine, or tri-tert-butylphosphine, for example) may beappropriately added in order to make the reaction efficiently proceed. Aquaternary ammonium salt, preferably tetrabutylammonium chloride ortetrabutylammonium bromide, for example, may also be appropriately addedin order to make the reaction efficiently proceed. In this reaction, apreferable result may be achieved in the presence of a base. The baseused at this time varies according to the starting material, the solventused and the like, and is not particularly limited. Preferable examplesof the base include sodium hydroxide, barium hydroxide, potassiumfluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesiumcarbonate and potassium phosphate. Under preferable reaction conditions,the reaction is completed in 1 to 24 hours, and the progress of thereaction can be monitored by a known chromatography technique. In thisreaction, the desired ester compound (8) can be efficiently obtainedeven when the compound (18a) is a halide or a trifluoromethanesulfonatecompound, wherein L₆ is a chlorine atom, a bromine atom, an iodine atomor a trifluoromethanesulfonate group, for example, and the compound (17)is a boronic acid compound or boronate compound, wherein L₄ is a boronicacid or boronate group, for example.

The reaction conditions in Sonogashira reaction vary according to thestarting material, the solvent and the transition metal catalyst, andare not particularly limited insofar as the conditions are similar tothose in this reaction. A method known to a person skilled in the artmay be used for the reaction. Preferably, a compound (17), wherein L₄represents a chlorine atom, a bromine atom, an iodine atom or asulfonate group such as a trifluoromethanesulfonate group, and 1.0 to5.0 equivalents of an alkyne compound (18b) with respect to the compound(17) are stirred in a solvent, for example. Preferable examples of thesolvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide. More preferable examplesof the solvent include tetrahydrofuran, 1,4-dioxane,1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere. Under preferable reaction conditions,the reaction is completed in 1 to 24 hours, and the progress of thereaction can be monitored by a known chromatography technique. Thetransition metal catalyst is preferably 0.01 to 0.5 equivalent withrespect to the compound (17) of a known palladium complex, and morepreferably a known palladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand(preferably triphenylphosphine, tri-o-tolylphosphine ortri-tert-butylphosphine, for example) may be appropriately added, forexample, in order to make the reaction efficiently proceed. In thereaction, a metal halide or a quaternary ammonium salt, preferablycopper (I) iodide, lithium chloride, tetrabutylammonium fluoride orsilver (I) oxide, for example, may be added. A preferable result may beachieved in the presence of a base. The base used here is notparticularly limited insofar as the base is used in a coupling reactionsimilar to this reaction. Preferable examples of the base include basicsolvents such as diethylamine, triethylamine, N,N-diisopropylethylamine,piperidine and pyridine.

In Stille coupling reaction, a trialkyltin compound (17), wherein L₄represents an alkyltin group, and 1.0 to 5.0 equivalents of a halide ora trifluoromethanesulfonate compound (18a), wherein L₆ represents achlorine atom, a bromine atom, an iodine atom or atrifluoromethanesulfonate group, with respect to the compound (17) arepreferably stirred in a solvent in the presence of 0.01 to 0.2equivalent of a transition metal catalyst with respect to the compound(17), for example. It is preferable to appropriately use 0.1 to 5.0equivalents of copper (I) halide or/and lithium chloride in order tomake the reaction efficiently proceed. Preferable examples of thesolvent used in this reaction include toluene, xylene,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone anddimethyl sulfoxide. The reaction temperature must be a temperature thatcan complete the coupling reaction, and is preferably room temperatureto 150° C. The preferable transition metal catalyst is a palladiumcomplex, preferably a known palladium complex such as palladium (II)acetate, dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0), for example, and morepreferably tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0), for example. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere. Under preferable reaction conditions,the reaction is completed in 1 to 24 hours, and the progress of thereaction can be monitored by a known chromatography technique.

[Preparation of Carbonyl Compound (6)]

The carbonyl compound (6) can be prepared from a compound (4) as astarting material according to Step 2-1, for example. Specifically, Step2-1 varies according to the starting material and is not particularlylimited insofar as the conditions are similar to those in this reaction.A method known to a person skilled in the art may be used for thereaction. For example, a compound (4) and 1.0 to 5.0 equivalents of acompound (5) with respect to the compound (4) are stirred in a solventin the presence or absence of 1.0 to 5.0 equivalents of a base withrespect to the compound (4) (see D. D. Davey et al., “J. Med. Chem.”,1991, vol. 39, p. 2671-2677). Preferable examples of the base usedinclude sodium hydride, sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium carbonate, cesium carbonate, barium carbonate,pyridine, lutidine and triethylamine. The solvent used varies accordingto the starting material, and is not particularly limited insofar as thesolvent does not inhibit the reaction and allows the starting materialto be dissolved therein to a certain extent. Preferable examples of thesolvent include acetonitrile, tetrahydrofuran, dimethyl sulfoxide,N,N-dimethylformamide and N-methylpyrrolidine. The base may optionallybe used as a solvent. The reaction temperature must be a temperaturethat can complete the reaction without promoting formation of anundesirable by-product, and is preferably room temperature to 150° C.,for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique or/and crystallization.

The carbonyl compound (6) can also be prepared from a compound (17) as astarting material according to Step 2-10, for example. Specifically,Step 2-10 varies according to the starting material and is notparticularly limited insofar as the conditions are similar to those inthis reaction. A method known to a person skilled in the art may be usedfor the reaction. For example, it is possible to use a two-stage methodof converting a compound (17), wherein L₄ represents a chlorine atom, abromine atom, an iodine atom or a sulfonate group such as atrifluoromethanesulfonate group, into a vinyl compound by Stillecoupling reaction using 1.0 to 5.0 equivalents of a vinyltin compoundwith respect to the compound (17) and then oxidizing the carboxylic acidby ozone oxidation reaction (see S. S. Chandran et al., “Bioorg. Med.Chem. Lett.”, 2001, vol. 11, p. 1493-1496, for example). It is alsopossible to use carbon monoxide insertion reaction using a transitionmetal catalyst (see T. Okano et al., “Bull. Chem. Soc. Jpn.”, 1994, vol.67, p. 2329-2332, for example).

[Preparation of Compound (4)]

The compound (4) is commercially available or can be obtained by atechnique known to a person skilled in the art. If not commerciallyavailable, the preferable compound (4), wherein L₃ represents a fluorineatom, a chlorine atom or a bromine atom, can be obtained by oxidizing acorresponding alcohol compound by an oxidation reaction known to aperson skilled in the art; or the carbonyl compound can be obtained byreducing a corresponding ester compound by a known reduction reaction.

[Preparation of Compound (5)]

The compound (5) used in this step is commercially available or can beobtained by a technique known to a person skilled in the art. (see M.Komoto et al., “Agr. Biol. Chem.”, 1968, vol. 32, p. 983-987; or J. M.Kokosa et al., “J. Org. Chem.”, 1983, vol. 48, p. 3605-3607, forexample).

[Preparation of Compound (7)]

In the formula R¹³, W, L₅ and V₁ are as defined above.

The above reaction formula shows an example of a method for preparingthe phosphonate compound (7). Specifically, the phosphonate compound (7)is commercially available or can be obtained by a method shown in theabove Step 3-1 to Step 3-3 and known to a person skilled in the art (seeC. Patois et al., “Synth. Commun.”, 1991, vol. 22, p. 2391; or J. A.Jackson et al., “J. Org. Chem.”, 1989, vol. 20, p. 5556, for example).Step 3-1 is a step of obtaining the desired phosphonate compound (7) bystirring a phosphonate compound (20a) and 1.0 to 2.0 equivalents of analkyl halide compound (19a) with respect to the phosphonate compound(20a) in a solvent in the presence of 1.0 to 1.5 equivalents of a basewith respect to the phosphonate compound (20a) to introduce R₁₃, forexample. Step 3-2 is a step of obtaining the desired phosphonatecompound (7) by stirring a phosphonate compound (19b) and 1.0 to 2.0equivalents of a halogenated formate compound (20b) with respect to thephosphonate compound (19b) in a solvent in the presence of 1.0 to 1.5equivalents of a base with respect to the phosphonate compound (19b).Step 3-3 is a step of obtaining the desired phosphonate compound (7) bystirring a phosphonic acid halide compound (19c) and 1.0 to 2.0equivalents of an ester compound (20c) with respect to the phosphonicacid halide compound (19c) in a solvent in the presence of 1.0 to 1.5equivalents of a base with respect to the phosphonic acid halidecompound (19c). The base used varies according to the starting materialand is not particularly limited. Preferable examples of the base includesodium hydride, n-butyl lithium, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide. Thesolvent used varies according to the starting material, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include hexane,toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide,hexamethylphosphoric triamide and a mixed solvent thereof. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferably −78°C. to 100° C. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique or/and crystallization. Thedesired phosphonate compound (7) can be efficiently obtained bymodification of R₁₃ by a technique known to a person skilled in the art.

The alkyl halide compound (19a), phosphonate compound (19b), phosphonicacid halide compound (19c), phosphonate compound (20a), halogenatedformate compound (20b) and ester compound (20c) used in this step arecommercially available or can be obtained by a technique known to aperson skilled in the art.

[Preparation of Compound (10)]

The compound (10) can be prepared from a compound (6) and a compound (9)according to Step 2-4. Specifically, Step 2-4 varies according to thestarting material and is not particularly limited insofar as theconditions are similar to those in this reaction. A method known to aperson skilled in the art may be used for the reaction (see Journal ofthe American Chemistry, 1961, vol. 83, p. 173, for example). Preferably,a compound (6) and 1.0 to 10.0 equivalents of a compound (9) withrespect to the compound (6) are stirred in a solvent in the presence of1.0 to 10.0 equivalents of a base with respect to the compound (6), forexample. The base used varies according to the starting material and isnot particularly limited. Preferable examples of the base includeorganic bases such as 1,8-diazabicyclo[5,4,0]-7-undecene anddiisopropylamine; and alkali metal salts such as potassium carbonate andsodium carbonate. The solvent used varies according to the startingmaterial, and is not particularly limited insofar as the solvent doesnot inhibit the reaction and allows the starting material to bedissolved therein to a certain extent. Preferable examples of thesolvent include hexane, toluene, diethyl ether, tetrahydrofuran,N,N-dimethylformamide, hexamethylphosphoric triamide and a mixed solventthereof. The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably −78° C. to 100° C. Under preferablereaction conditions, the reaction is completed in 1 to 24 hours, and theprogress of the reaction can be monitored by a known chromatographytechnique. An undesirable by-product can be removed by a technique knownto a person skilled in the art such as a conventional chromatographytechnique or/and crystallization.

[Preparation of Compound (9)]

The compound (9) used in this step is commercially available or can beobtained by a technique known to a person skilled in the art.

[Preparation of Compound (11)]

The compound (11) used in this step is commercially available or can beobtained by a technique known to a person skilled in the art.

[Preparation of Amine Compound (13)]

The amine compound (13) is commercially available or can be obtained bya technique known to a person skilled in the art. Preferably, thecompound can be prepared from a nitro compound (12) as a startingmaterial according to Step 2-6. Specifically, reduction reaction in Step2-6 varies according to the starting material and is not particularlylimited insofar as the conditions are similar to those in this reaction.A method known to a person skilled in the art may be used for thereaction (see Shin Jikken Kagaku Koza (New Courses in ExperimentalChemistry), vol. 14, Yuki Kagobutsu No Gosei To Hannou (Synthesis andReaction of Organic Compounds) [III], edited by The Chemical Society ofJapan, Maruzen Co., Ltd., February 1978, p. 1333-1341, for example). Thereaction is preferably a catalytic reduction method using a metalcatalyst or a reduction method using a metal, for example. The catalyticreduction method is preferably performed in a hydrogen atmosphere atnormal pressure to 100 atm. Preferable examples of the metal catalystused in this reaction include platinum, platinum oxide, platinum black,Raney nickel and palladium-carbon. The solvent used in the presentreaction varies according to the starting material, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include methanol,ethanol, diethyl ether, tetrahydrofuran, methylene chloride, chloroformand ethyl acetate. An acidic substance such as acetic acid orhydrochloric acid may be appropriately added in order to make thereaction efficiently proceed. The reduction method using a metalpreferably employs zinc, iron or tin, for example, and is preferablyperformed under acidic conditions using hydrochloric acid, acetic acidor ammonium chloride, for example. The solvent used in the presentreaction varies according to the starting material, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include methanol,ethanol and 2-propanol. The reaction temperature must be a temperaturethat can complete the reaction without promoting formation of anundesirable by-product, and is preferably room temperature to 100° C.Under preferable reaction conditions, the reaction is completed in 1 to24 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique or/and crystallization.

The preferable amine compound (13) can also be prepared from a compound(15) as a starting material which is commercially available or can beobtained by a technique known to a person skilled in the art, accordingto coupling reaction in Step 2-8. Specifically, the coupling reaction inStep 2-8 varies according to the starting material and is notparticularly limited insofar as the conditions are similar to those inthis reaction. A method known to a person skilled in the art may be usedfor the reaction. Preferably, for example, it is possible to use atwo-stage method of performing coupling reaction of benzophenone imineusing a transition metal catalyst and then performing a knownbenzophenone removal reaction treatment (see S. L. Buchwald et al.,“Tetrahedron Lett.”, 1997, vol. 38, p. 6367-6370; or J. F. Hartwig etal., “J. Am. Chem. Soc.”, 1998, vol. 120, p. 827-828, for example). Inthe coupling reaction of benzophenone imine, a compound (15) and 1.0 to10.0 equivalents of benzophenone imine with respect to the compound (15)are stirred in a solvent in the presence of 0.01 to 0.2 equivalent of acatalyst with respect to the compound (15). Preferable examples of thecatalyst that can be used include known palladium complexes such aspalladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) andtris(dibenzylideneacetone)dipalladium (0); and known nickel catalystssuch as (1,5-cyclooctadiene)nickel (0). Preferably, a phosphorus ligandsuch as triphenylphosphine, tri-o-tolylphosphine,tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,2-bis(diphenylphosphino)ethane or 1,1′-bis(diphenylphosphino)ferrocenemay be appropriately added in order to make the reaction efficientlyproceed, for example. A preferable result may be achieved in thepresence of a base. The base used is not particularly limited insofar asthe base is used in a coupling reaction similar to this reaction.Preferable examples of the base include sodium hydroxide, bariumhydroxide, potassium fluoride, cesium fluoride, sodium carbonate,potassium carbonate, cesium carbonate, potassium phosphate and sodiumtert-butoxide. The solvent used varies according to the startingmaterial and the transition metal catalyst used, and is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 100° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere. A method known to aperson skilled in the art may be used for the treatment after the secondstage (see T. W. Green, “Protective Groups in Organic Synthesis”, JohnWiley & Sons, Inc., 1981). An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique or/and crystallization.

In the preferable amine compound (13), L₄ can be modified by a methodknown to a person skilled in the art, and a hydrogen atom in L₄ can bepreferably converted into a halogen substituent (see Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol. 14, Yuki Kagobutsu NoGosei To Hannou (Synthesis and Reaction of Organic Compounds) [I],edited by The Chemical Society of Japan, Maruzen Co., Ltd., November1977, p. 354-360, for example).

[Preparation of Nitro Compound (12)]

The nitro compound (12) is commercially available or can be obtained bya technique known to a person skilled in the art. If not commerciallyavailable, the preferable compound (12), wherein L₄ represents afluorine atom, a chlorine atom, a bromine atom or an iodine atom, can beefficiently obtained from a corresponding precursor by a nitrationreaction known to a person skilled in the art (see Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol. 14, Yuki Kagobutsu NoGosei To Hannou (Synthesis and Reaction of Organic Compounds) [III],edited by The Chemical Society of Japan, Maruzen Co., Ltd., February1978, p. 1261-1300, for example).

[Preparation of Compound (17)]

The compound (17) can be obtained by a technique known to a personskilled in the art. Preferably, the compound (17) can be prepared i)from a compound (15) as a starting material according to Step 2-9 or ii)from an amine compound (13) as a starting material according to Step2-7, for example.

In the case of i), Step 2-9 is performed by the same method as in theabove Step 2-1.

In the case of ii), an amine compound (13) can be efficiently convertedinto the compound (17) in Step 2-7 by treating the amine compound (13)with a mixed solvent of acetic anhydride and formic acid in a firststage, condensing the compound with a compound (14) under basicconditions in a second stage, and heating the condensate with ammoniumacetate and acetic acid in a third stage, for example. In the firststage, a compound (13) is stirred in a mixed solvent of 2.0 to 10.0equivalents of acetic anhydride with respect to the compound (13) and10.0 to 20.0 equivalents of formic acid with respect to the compound(13) at ice-cold temperature to 50° C. In the second stage, 1.0 to 5.0equivalents of a base is preferably used with respect to the compound(13). Examples of the base include sodium hydride, sodium hydroxide,potassium hydroxide, lithium hydroxide, n-butyl lithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide and sodiumbis(trimethylsilyl)amide. The solvent used in the present reactionvaries according to the starting material, and is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent include diethyl ether,tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide.Preferably, potassium iodide or sodium iodide may be added, for example,in order to make the reaction efficiently proceed. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferably roomtemperature to 100° C., for example. In the third stage, the condensateis preferably treated in a mixture of 5.0 to 10.0 equivalents ofammonium acetate with respect to the compound (13) and 10.0 to 20.0equivalents of acetic acid with respect to the compound (13) at 50 to100° C. Under preferable reaction conditions, the reaction is completedin 1 to 24 hours, and the progress of the reaction can be monitored by aknown chromatography technique. An undesirable by-product can be removedby a technique known to a person skilled in the art such as aconventional chromatography technique or/and crystallization.

The compound (14) used in the second stage of this step is commerciallyavailable or can be obtained by a technique known to a person skilled inthe art. If not commercially available, the preferable compound (14) canbe prepared from a corresponding carbonyl compound by a halogenationreaction known to a person skilled in the art (see Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol. 19, Yuki Gosei(Organic Synthesis) [I], edited by The Chemical Society of Japan,Maruzen Co., Ltd., June 1992, p. 363-482, for example).

L₄ in the compound (17) can be modified by a technique known to a personskilled in the art, and can be preferably converted into, for example,an iodine group (see S. L. Buchwald et al., “J. Am. Chem. Soc.”, 2002,vol. 124, p. 14844-14845, for example), a lower alkyltin group (see J.Marti et al., “Synth. Commun.”, 2000, vol. 30, p. 3023-3030, forexample) or a boron group (see N. Miyaura et al., “J. Org. Chem.”, 1995,vol. 60, p. 7508-7510, for example). The compounds (18a) and (18b) arecommercially available or can be obtained by a technique known to aperson skilled in the art.

The compound of the general formula (I-9), general formula (I-4) orgeneral formula (I-6), wherein two of R¹⁰, R¹¹ and R¹² form a ring, canbe prepared from the compound (2a) as a starting material, wherein R¹⁰and R¹¹ form a ring, by the same method as above. When the method asabove is performed using the compound (2a) as a starting material,wherein R¹⁰ or R¹¹ represents an alkyl group substituted with a halogenatom such as a chlorine atom, a bromine atom or an iodine atom, thecompound of the general formula (I-9), general formula (I-4) or generalformula (I-6), wherein two of R¹⁰, R¹¹ and R¹² form a ring, can beprepared in Step 1-2, Step 1-5, Step 1-6 or Step 1-7.

[General Preparation Method 2]

Typically used General Preparation Method 2 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-3, III-4,III-6, III-7 or III-8):

is a partial structure corresponding to the above-described Het, whereinAr₁, Ar₂, X₁, X₄, X₅, X₆, Y₁₀, Y₁₁, R¹⁰, R¹¹, R¹², nd, ne, ni, nj and niare as defined above; Y₁₃ represents a carboxyl group, an ester group, athioester group, a dithioester group, a nitrile group, a thioimino ethergroup or an iminoether group; Y₁₄ represents an oxygen atom, a nitrogenatom or a sulfur atom; and P₁ represents a protecting group for an aminogroup such as a methyl carbamate group, a benzyl carbamate group, atert-butyl carbamate group, an allyl group, an acetyl group or a formylgroup.

The above General Preparation Method 2 includes a method of reacting acompound (1a) with an amine compound (23a) or amine compound (23b)according to Step 4-1 or Step 4-5 to convert the compound (1a) into acompound (24) or compound (26), or converting a compound (1a) into acompound (24) or compound (26) according to Step 4-9 or Step 4-10 whichis a three-stage reaction including deprotection, and further reactingthe resulting compound (24) or compound (26) with ammonia, an ammoniumsalt or formamide in Step 4-2 or Step 4-6 to prepare a compound of thegeneral formula (I-9), the general formula (I-4), the general formula(I-6), the general formula (I-7) or the general formula (I-8); a methodof once converting a compound (24) or compound (26) into an oxazolecompound (25) or a compound (27) by dehydration reaction in Step 4-3 orStep 4-7, and then reacting the oxazole compound (25) or the compound(27) with ammonia, an ammonium salt, formamide or an amine compound (22)in Step 4-4, Step 4-8 or Step 4-12 to prepare a compound of the generalformula (I-9), the general formula (I-4), the general formula (I-6), thegeneral formula (I-7) or the general formula (I-8); and a method ofreacting a compound (1a) with an amine compound (23a) according to Step4-11 to prepare a compound of the general formula (I-9), the generalformula (I-6), the general formula (I-7) or the general formula (I-8).

[Preparation of Compound of General Formula (I-4)]

The compound of the general formula (I-4) can be prepared by i) reactinga compound (26) in the presence of an acid or base and optionally in thepresence of ammonia, an ammonium salt, formamide or the like accordingto Step 4-6. The compound can also be prepared by ii) reacting acompound (25) or compound (27) with an amine compound (22), ammonia, anammonium salt, formamide or the like according to Step 4-4 or Step 4-8.

The method i), specifically, Step 4-6 varies according to the startingmaterial and is not particularly limited insofar as the conditions aresimilar to those in this reaction. A known method described in manydocuments may be used for the reaction (see Heterocyclic Compounds, Vol.5, Wiley, New York, N.Y. 1957, p. 503; and Journal of HeterocyclicChemistry, 1982, vol. 19, p. 193, for example). Preferably, a compound(26), wherein Y₁₄ represents an oxygen atom or a sulfur atom, is stirredin a solvent in the presence of 1.0 to 100.0 equivalents of ammonia, anammonium salt such as ammonium acetate or ammonium carbonate orformamide with respect to the compound (26), for example. The solventused is not particularly limited insofar as the solvent does not inhibitthe reaction and allows the starting material to be dissolved therein toa certain extent. Preferable examples of the solvent include ethersolvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as amyl alcohol and isopropyl alcohol;polar solvents such as N,N-dimethylformamide and N-methylpyrrolidone;nonpolar solvents such as toluene, benzene and dichlorobenzene; organicacids such as acetic acid; water; and a mixture thereof. Formamide maybe used as a solvent. The reaction temperature must be a temperaturethat can complete the reaction without promoting formation of anundesirable by-product, and is preferably room temperature to 200° C.,for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

Alternatively, a compound (26), wherein Y₄ represents a nitrogen atom,is stirred in a solvent in the presence or absence of 0.1 to 10equivalents of an acid, base or organic salt with respect to thecompound (26). Preferable examples of the acid, base or organic saltused include inorganic acids such as hydrochloric acid and sulfuricacid; organic acids, such as p-toluenesulfonic acid and methanesulfonicacid; organic bases such as pyridine and dimethylamino pyridine; andorganic salts such as pyridinium p-toluenesulfonate andtetrabutylammonium hydroxide. The solvent used is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent that can be used include ethersolvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as methanol, ethanol, amyl alcohol andisopropyl alcohol; polar solvents such as N,N-dimethylformamide andN-methylpyrrolidone; nonpolar solvents such as toluene, benzene anddichlorobenzene; water; and a mixture thereof. The above acid, base ororganic salt may be used as a solvent. The reaction temperature must bea temperature that can complete the reaction without promoting formationof an undesirable by-product, and is preferably room temperature to 200°C., for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

The method ii), specifically, Step 4-4 or Step 4-8 varies according tothe starting material and is not particularly limited insofar as theconditions are similar to those in this reaction. A known methoddescribed in many documents may be used for the reaction (seeHeterocyclic Compounds, vol. 5, Wiley, New York, N.Y. 1950, p. 214; andThe Journal of Organic Chemistry, 1962, vol. 27, p. 3240, for example).For example, an oxazole compound (25) or a compound (27) and 1.0 to100.0 equivalents of an amine compound (22), ammonia, an ammonium saltsuch as ammonium acetate or ammonium carbonate or formamide with respectto the compound (25) or compound (27) are stirred in a solvent. Thesolvent used is not particularly limited insofar as the solvent does notinhibit the reaction and allows the starting material to be dissolvedtherein to a certain extent. Preferable examples of the solvent includeether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as amyl alcohol and isopropyl alcohol;polar solvents such as N,N-dimethylformamide and N-methylpyrrolidone;nonpolar solvents such as toluene, benzene and dichlorobenzene; organicacids such as acetic acid; water; and a mixture thereof. The aminesource to be reacted may be used as a solvent. The reaction temperaturemust be a temperature that can complete the reaction without promotingformation of an undesirable by-product, and is preferably roomtemperature to 200° C., for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization. The amine compound (22) used in thisstep is commercially available or can be obtained by a technique knownto a person skilled in the art.

[Preparation of Compound of General Formula (I-9), General Formula(I-6), General Formula (I-7) and General Formula (I-8)]

The compound of the general formula (I-9), the general formula (I-6),the general formula (I-7) or the general formula (I-8) can be preparedby i) reacting a compound (24) or compound (25) in the presence ofammonia, an ammonium salt, formamide or the like according to Step 4-2or Step 4-12. The compound can also be prepared by ii) reacting acompound (1a) with an amine compound (23a) according to Step 4-11.

The method i), specifically, Step 4-2 or Step 4-12 is the same method asin Step 4-6.

The method ii), specifically, Step 4-11 varies according to the startingmaterial and is not particularly limited insofar as the conditions aresimilar to those in this reaction. A known method described in manydocuments may be used for the reaction (see Journal of the ChemicalSociety, 1962, p. 5149; and Journal of Medicinal Chemistry, 1983, vol.26, p. 1187, for example). For example, a compound (1a), wherein Y¹³represents a nitrile group, a thioimino ether group or an imino ethergroup, and 1.0 to 5.0 equivalents of an amine compound (23a) withrespect to the compound (1a) are stirred in a solvent. The solvent usedis not particularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include ethersolvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as methanol, ethanol, butanol, amylalcohol and isopropyl alcohol; polar solvents such asN,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents such astoluene, benzene and dichlorobenzene; organic acids such as acetic acid;water; and a mixture thereof. The yield may be improved when performingreaction in the presence of 1.0 to 10.0 equivalents of an organic aminesuch as triethylamine, diisopropylamine or pyridine or an alkali metalsalt such as potassium carbonate or sodium carbonate with respect to thecompound (1a). The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably room temperature to 200° C., for example.Under preferable reaction conditions, the reaction is completed in 1 to72 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

[Preparation of Compound (24) and Compound (26)]

The compound (24) or compound (26) can be prepared by reacting acompound (1a) with an amine compound (23a) or amine compound (23b)according to Step 4-1 or Step 4-5. Specifically, Step 4-1 or Step 4-5varies according to the starting material and is not particularlylimited insofar as the conditions are similar to those in this reaction.A known method described in many documents may be used for the reaction(see Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry),vol. 22, Yuki Gosei (Organic Synthesis) [IV], edited by The ChemicalSociety of Japan, Maruzen Co., Ltd., November 1992, p. 137-163; andOrganic Synthesis, 1941, I, p. 5, for example). For example, a compound(1a), wherein Y₁₃ represents a carboxyl group, and 1.0 to 10.0equivalents of a compound (23a) or compound (23b) with respect to thecompound (1a) are stirred in a solvent in the presence of 0.1 to 10.0equivalents of a condensing agent with respect to the compound (1a). Thecondensing agent used varies according to the starting material and isnot particularly limited. Preferable examples of the condensing agentinclude inorganic acids such as hydrochloric acid and sulfuric acid;organic acids such as p-toluenesulfonic acid and methanesulfonic acid,1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,diethyl cyanophosphonate and bis(2-oxo-3-oxazolidinyl)phosphonicchloride. Preferably, 1.0 to 5.0 equivalents of N-hydroxysuccinimide,N-hydroxybenzotriazole or dimethylaminopyridine may be added withrespect to the compound (1a) in order to make the reaction efficientlyproceed, for example. The solvent used varies according to the startingmaterial and the condensing agent used, and is not particularly limitedinsofar as the solvent does not inhibit the reaction and allows thestarting material to be dissolved therein to a certain extent.Preferable examples of the solvent include halogenated solvents such aschloroform, methylene chloride and 1,2-dichloroethane; and polarsolvents such as tetrahydrofuran and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferablyice-cold temperature to 150° C., for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography techniqueor/and crystallization.

Alternatively, a compound (1a), wherein Y₁₃ represents a cyano group, animino ether group or a thioimino ether group, and 1.0 to 100.0equivalents of an amine compound (23a) or amine compound (23b) withrespect to the compound (1a) are stirred in a solvent. The solvent usedis not particularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include ethersolvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; alcohol solvents such as methanol, ethanol and isopropylalcohol; polar solvents such as N,N-dimethylformamide andN-methylpyrrolidone; nonpolar solvents such as toluene, benzene anddichlorobenzene; organic acids such as acetic acid; organic bases suchas pyridine; water; and a mixture thereof. The amine compound (23a) oramine compound (24b) may be used as a solvent. The yield may be improvedwhen using 0.1 to 1.0 equivalent of an inorganic acid such ashydrochloric acid, a Lewis acid such as trifluoroborate or an organicacid such as p-toluenesulfonic acid with respect to the compound (1a) orwhen using 1.0 to 10.0 equivalents of an organic base such astriethylamine, pyridine or diisopropylethylamine with respect to thecompound (1a). The reaction temperature must be a temperature that cancomplete the reaction without promoting formation of an undesirableby-product, and is preferably 0 to 200° C., for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

The compound (24) or compound (26) can also be prepared from a compound(1a) according to Step 4-9 or Step 4-10. Specifically, Step 4-9 or Step4-10 consists of a three-stage reaction including a deprotection step.In a first stage, a compound (1a) is condensed with a compound (23c) orcompound (23d) by dehydration. In a second stage, the protecting groupis deprotected. In a third stage, the condensate is condensed with acompound (23e).

The first-stage condensation reaction may be performed by the samemethod as in Step 4-1. The second-stage deprotection reaction variesaccording to the starting material and is not particularly limitedinsofar as the conditions are similar to those in this reaction. A knownmethod described in many documents may be used for the reaction (see T.W. Green, “Protective Groups in Organic Synthesis”, John Wiley & Sons,Inc., 1999, p. 615-626). Preferably, the condensation compound in thefirst stage, wherein P₁ represents a tert-butyl carbamate group, isstirred in a solvent in the presence of 1.0 to 100.0 equivalents of anacid with respect to the compound, for example. Examples of the acidused include inorganic acids such as hydrochloric acid and sulfuricacid; and organic acids such as trifluoroacetic acid and methanesulfonicacid. The solvent used is not particularly limited insofar as thesolvent does not inhibit the reaction and allows the starting materialto be dissolved therein to a certain extent. Preferable examples of thesolvent include ethyl acetate, methanol, ethanol, 1,4-dioxane, methylenechloride, chloroform, methanol, isopropyl alcohol, N,N-dimethylformamideand N-methylpyrrolidone. The reaction temperature must be a temperaturethat can complete the reaction without promoting formation of anundesirable by-product, and is preferably 0 to 100° C., for example.Under preferable reaction conditions, the reaction is completed in 1 to24 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

The third-stage condensation reaction may be performed by the samemethod as in Step 4-1.

[Preparation of Compound (1a)]

The compound (1a) can be prepared from a compound (4) or compound (17)by the same method as in the above Step 2-1 or Step 2-10.

[Preparation of Compound (25) and Compound (27)]

The compound (25) or compound (27) can be prepared from the compound(24) or compound (26) by dehydration reaction according to Step 4-3 orStep 4-7. Specifically, Step 4-3 or Step 4-7 varies according to thestarting material and is not particularly limited insofar as theconditions are similar to those in this reaction. A known methoddescribed in many documents may be used for the reaction (see TheChemistry of Heterocyclic Compounds, 45; Wiley, New York, 1986, p. 1,for example). For example, the compound (24) or compound (26) is stirredin a solvent in the presence of 1.0 to 100.0 equivalents of adehydration reagent with respect to the compound (24) or compound (26).The dehydration reagent used varies according to the starting materialand is not particularly limited. Preferable examples of the dehydrationreagent include phosphorus oxychloride, thionyl chloride, phosgene,triphosgene, carbonyldiimidazole, hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, methanesulfonic acid, triphenylphosphine-carbontetrachloride and triphenylphosphine-carbon tetrabromide. The solventused is not particularly limited insofar as the solvent does not inhibitthe reaction and allows the starting material to be dissolved therein toa certain extent. Preferable examples of the solvent include ethersolvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether;halogenated solvents such as methylene chloride, 1,2-dichloroethane andchloroform; polar solvents such as N,N-dimethylformamide andN-methylpyrrolidone; nonpolar solvents such as toluene, benzene anddichlorobenzene; and a mixture thereof. The dehydration reagent may beused as a solvent. The reaction temperature must be a temperature thatcan complete the reaction without promoting formation of an undesirableby-product, and is preferably 0 to 200° C., for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

[Preparation of Compound (23a), Compound (23b), Compound (23c), Compound(23d) and Compound (23e)]

The compound (23a), compound (23b), compound (23c), compound (23d) andcompound (23e) are commercially available or can be obtained by atechnique known to a person skilled in the art.

[General Preparation Method 3]

Typically used General Preparation Method 3 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-4, III-5,III-7 or III-8):

is a partial structure corresponding to the above-described Het, whereinAr₁, Ar₂, X₁, X₅, X₆, Y₁₀, Y₁₁, R¹⁰, R¹¹, R¹², L₂, L₄, nd, ne, ni and njare as defined above; and Pr represents a protecting group for aheterocycle nitrogen atom such as a trityl group, a methoxymethyl group,a benzyl group or a methanesulfonic acid group.

The above General Preparation Method 3 includes a method of reacting acompound (17) with a heterocyclic compound (28) in Step 5-1 to prepare acompound of the general formula (I-4), the general formula (I-7) or thegeneral formula (I-8); and a method of reacting a compound (17) with aheterocyclic compound (29) having a protecting group in Step 5-2 to onceconvert the compound (17) into a compound of the general formula (I-5)having a protecting group and then deprotecting the protecting group ofthe compound of the general formula (I-5) and subsequently reacting thecompound with a compound (2b) in Step 5-3 to prepare a compound of thegeneral formula (I-4), the general formula (I-7) or the general formula(I-8).

[Preparation of compounds of General Formula (I-4) and (I-5)]

The compound of the general formula (I-4) or (I-5) can be prepared by i)reacting a compound (17) with a compound (28) or compound (29) accordingto Step 5-1 or Step 5-2. The compound of the general formula (I-4) canalso be prepared by ii) deprotecting the protecting group of thecompound of the general formula (I-5) and then reacting the compoundwith a compound (2b) according to Step 5-3.

The method i), specifically, Step 5-1 or Step 5-2 varies according tothe starting material and is not particularly limited insofar as theconditions are similar to those in this reaction. A known methoddescribed in many documents such as Mizoroki-Heck reaction (see R. F.Heck, “Org. Reactions.”, 1982, vol. 27, p. 345, for example) orSonogashira reaction (see K. Sonogashira, “Comprehensive OrganicSynthesis”, 1991, vol. 3, p. 521, for example) may be used for thereaction.

In Mizoroki-Heck reaction, a compound (17), wherein L₄ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of acompound (28) or compound (29), wherein X₁ represents an alkenyl group,with respect to the compound (17) are stirred in a solvent in thepresence of 0.01 to 0.5 equivalent of a transition metal catalyst withrespect to the compound (17), for example. The transition metal catalystused is preferably a palladium complex, for example, and more preferablya known palladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or2-(di-tert-butylphosphino)biphenyl may be preferably added, for example,in order to make the reaction efficiently proceed. A preferable resultmay be achieved in the presence of a base. The base used is notparticularly limited insofar as the base is used in a coupling reactionsimilar to this reaction. Preferable examples of the base includetriethylamine, N,N-diisopropylethylamine, N,N-dicyclohexylmethylamineand tetrabutylammonium chloride. The solvent used varies according tothe starting material and the transition metal catalyst used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Sonogashira reaction, a compound (17), wherein L₄ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of acompound (28) or compound (29), wherein X₁ represents an alkynyl group,with respect to the compound (17) are stirred in a solvent in thepresence of 0.01 to 0.5 equivalent of a transition metal catalyst withrespect to the compound (17), for example. The transition metal catalystused is preferably a known palladium complex, for example, and morepreferably a known palladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine or tri-tert-butylphosphine maybe preferably added, for example, in order to make the reactionefficiently proceed. In the reaction, a good result may be achieved whenadding a metal halide or a quaternary ammonium salt, preferably copper(I) iodide, lithium chloride, tetrabutylammonium fluoride or silver (I)oxide, for example. A preferable result may be achieved in the presenceof a base. The base used here is not particularly limited insofar as thebase is used in a coupling reaction similar to this reaction. Preferableexamples of the base include diethylamine, triethylamine,N,N-diisopropylethylamine, piperidine and pyridine. Preferable examplesof the solvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide. More preferable examplesof the solvent include tetrahydrofuran, 1,4-dioxane,1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

The method ii), specifically, Step 5-3 consists of first-stagedeprotection reaction and second-stage reaction with a compound (2b).The first-stage deprotection reaction varies according to the startingmaterial and is not particularly limited insofar as the conditions aresimilar to those in this reaction. A known method described in manydocuments may be used for the reaction (see T. W. Green, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons, Inc., 1999, p.615-626). Preferably, the compound of the general formula (I-5) isstirred in a solvent in the presence of 1.0 to 100.0 equivalents of anacid or base with respect to the compound of the general formula (I-5),for example. Preferable Examples of the acid used include inorganicacids such as hydrochloric acid and sulfuric acid; and organic acidssuch as trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonicacid. Preferable examples of the base used include alkali metalhydroxides such as sodium hydroxide and potassium hydroxide; alkalimetal carbonates such as potassium carbonate and sodium carbonate; andorganic amines such as ammonia and methylamine. The solvent used is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate,methanol, ethanol, benzene, toluene, xylene, chloroform, methylenechloride, water and a mixed solvent thereof. The acid or base may beused as a solvent. The reaction temperature must be a temperature thatcan complete the deprotection reaction, and is preferably roomtemperature to 150° C., for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization. The second stage reaction of thecompound (I-5) with the compound (2b) may be performed by the samemethod as in Step 1-3.

[Preparation of Compound (28)]

In the formula, X₁, Y₁₀, Y₁₁, Y₁₄, R¹⁰, R¹¹ and R¹² are as definedabove; L₇ represents a hydrogen atom, a halogen atom such as a chlorineatom, a bromine atom or an iodine atom, a sulfonate group such as atrifluoromethanesulfonate group, a trialkyltin group or a leaving groupsuch as a boronic acid or boronate group; and Y₁₅ represents an oxygenatom, or a nitrogen atom which may be substituted with a substituentselected from the above Substituent Group A1.

The compound (28) can be prepared by i) condensing a compound (31) withan alkene or alkyne compound according to Step 6-1. The compound (28)can also be prepared by ii) cyclizing a compound (32) according to Step6-2.

The method i), specifically, Step 6-1 varies according to the startingmaterial and is not particularly limited insofar as the conditions aresimilar to those in this reaction. A known method described in manydocuments such as Mizoroki-Heck reaction (see R. F. Heck, “Org.Reactions.”, 1982, vol. 27, p. 345, for example), Suzuki-Miyaurareaction (see A. Suzuki, “Chem. Rev.”, 1995, vol. 95, p. 2457, forexample), Sonogashira reaction (see K. Sonogashira, “ComprehensiveOrganic Synthesis”, 1991, vol. 3, p. 521) or Stille coupling reaction(see J. K. Stille, “Angew. Chem. Int. Ed. Engl.”, 1986, vol. 25, p. 508,for example) may be used for the reaction.

In Mizoroki-Heck reaction, a compound (31), wherein L₇ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of analkene compound, wherein the alkene compound refers to a compound havinga double bond in the molecule, with respect to the compound (31) arestirred in a solvent in the presence of 0.01 to 0.2 equivalent of atransition metal catalyst with respect to the compound (31), forexample. The transition metal catalyst used is preferably a palladiumcomplex, for example, and more preferably a known palladium complex suchas palladium (II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or2-(di-tert-butylphosphino)biphenyl may be preferably added, for example,in order to make the reaction efficiently proceed. A preferable resultmay be achieved in the presence of a base. The base used is notparticularly limited insofar as the base is used in a coupling reactionsimilar to this reaction. Preferable examples of the base includetriethylamine, N,N-diisopropylethylamine, N,N-dicyclohexylmethylamineand tetrabutylammonium chloride. The solvent used varies according tothe starting material and the transition metal catalyst used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Suzuki-Miyaura reaction, a compound (31), wherein L₇ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of analkene or alkyne boronic acid or boronate compound, wherein the boronicacid or boronate compound refers to a boronic acid or boronate compounddirectly bonded to a double bond or triple bond, with respect to thecompound (31) are stirred in a solvent in the presence of 0.01 to 0.5equivalent of a transition metal catalyst with respect to the compound(31), for example. The transition metal catalyst used is preferably aknown palladium complex, and more preferably a known palladium complexsuch as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine ortri-tert-butylphosphine may be preferably added, for example, in orderto make the reaction efficiently proceed. A quaternary ammonium salt,preferably tetrabutylammonium chloride or tetrabutylammonium bromide,for example, may also be added in order to make the reaction efficientlyproceed. In this reaction, a preferable result may be achieved in thepresence of a base. The base used at this time varies according to thestarting material, the solvent used and the like, and is notparticularly limited. Preferable examples of the base include sodiumhydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodiumcarbonate, potassium carbonate, cesium carbonate and potassiumphosphate. The solvent used varies according to the starting materialand the transition metal catalyst used, and is not particularly limitedinsofar as the solvent does not inhibit the reaction and allows thestarting material to be dissolved therein to a certain extent.Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide, water and a mixedsolvent thereof. The reaction temperature must be a temperature that cancomplete the coupling reaction, and is preferably room temperature to200° C., for example. This reaction is performed preferably in an inertgas atmosphere, and more preferably in a nitrogen or argon atmosphere,for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization. The desired compound (28) can also be obtained from acombination of the boronic acid compound or boronate compound (31),wherein L₇ represents a boronic acid group or a boronate group, with ahalogenated alkene compound or an enol trifluoromethanesulfonatecompound by the same method as above.

In Sonogashira reaction, a compound (31), wherein L₇ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of analkyne compound, wherein the alkyne compound refers to a compound havingHC≡C— in the molecule, with respect to the compound (31) are stirred ina solvent in the presence of 0.01 to 0.5 equivalent of a transitionmetal catalyst with respect to the compound (31), for example. Thetransition metal catalyst used is preferably a known palladium complex,for example, and more preferably a known palladium complex such aspalladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine or tri-tert-butylphosphine maybe preferably added, for example, in order to make the reactionefficiently proceed. In the reaction, a good result may be achieved whenadding a metal halide or a quaternary ammonium salt, preferably copper(I) iodide, lithium chloride, tetrabutylammonium fluoride or silver (I)oxide, for example. A preferable result may be achieved in the presenceof a base. The base used here is not particularly limited insofar as thebase is used in a coupling reaction similar to this reaction. Preferableexamples of the base include diethylamine, triethylamine,N,N-diisopropylethylamine, piperidine and pyridine. Preferable examplesof the solvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide. More preferable examplesof the solvent include tetrahydrofuran, 1,4-dioxane,1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Stille coupling reaction, a compound (31), wherein L₇ represents achlorine atom, a bromine atom, an iodine atom or atrifluoromethanesulfonate group, and 1.0 equivalent or more of atrialkyltin compound, wherein the trialkyltin compound refers to analkyltin compound directly bonded to a double bond or triple bond, withrespect to the compound (31) are stirred in a solvent in the presence of0.01 to 0.2 equivalent of a transition metal catalyst with respect tothe compound (31), for example. The transition metal catalyst used ispreferably a palladium complex, for example, and more preferably a knownpalladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). In order to make the reactionefficiently proceed, 0.1 to 5.0 equivalents of copper (I) halide or/andlithium chloride may be added. Preferable examples of the solvent usedinclude toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone and dimethyl sulfoxide. The reaction temperaturemust be a temperature that can complete the coupling reaction, and ispreferably room temperature to 150° C., for example. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere, for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization. The desired compound (28) can also beobtained from a combination of the tin compound (31), wherein L₇represents a trialkyltin group, with a halogenated alkene compound orenol trifluoromethanesulfonate compound by the same method as above. Thehalogenated alkene compound refers to a compound of which the hydrogenatom bonded to the double bond in the molecule is replaced by a halogenatom. The enol trifluoromethanesulfonate compound refers to a compoundof which the hydrogen atom of the enol ester group in the molecule isreplaced by a trifluoromethanesulfonyl group.

The method ii), specifically, Step 6-2 may be performed by the samemethod as in Step 4-2 or Step 4-6.

[Preparation of Compound (31)]

The compound (31) is commercially available or prepared by a methodknown to a person skilled in the art. If not commercially available, thecompound (31), wherein L₇ is a boronic acid group or a boronate group,can be prepared by a method known to a person skilled in the art, forexample, although the method varies according to the starting material(see Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry),vol. 22, Yuki Gosei (Organic Synthesis) [VI], edited by The ChemicalSociety of Japan, Maruzen Co., Ltd., September 1992, p. 61-90, forexample). The compound (31), wherein L₇ is a trialkyltin group, can beprepared by a method known to a person skilled in the art, although themethod varies according to the starting material (see Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol. 22, Yuki Gosei(Organic Synthesis) [VI], edited by The Chemical Society of Japan,Maruzen Co., Ltd., September 1992, p. 179-201, for example).

[Preparation of Compound (32)]

The compound (32) is commercially available or prepared by a methodknown to a person skilled in the art. If not commercially available, thecompound (32) can be prepared by the same method as in Step 1-1 or Step4-1, for example.

[Preparation of Compound (29)]

The compound (29) is commercially available or can be prepared by thesame method as in the case of the compound (28) if not commerciallyavailable.

The compound of the general formula (I-7) or the general formula (I-8)can be prepared from the compound (28) or compound (29), wherein two ofR¹⁰, R¹¹ and R¹² form a ring, as a starting material by the same methodas above.

[General Preparation Method 4]

Typically used General Preparation Method 4 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-4, III-5,III-7 or III-8):

is a partial structure corresponding to the above-described Het, whereinAr₁, Ar₂, X₁, X₅, X₆, Y₁₀, Y₁₁, R¹⁰, R¹¹, R¹², L₂, Pr, nd, ne, ni and njare as defined above; and L₇ and L₇′ each represent a halogen atom suchas hydrogen, chlorine, bromine or iodine, a sulfonate group such as atrifluoromethanesulfonate group or a trialkyltin group or a leavinggroup such as a boron acid or boronate group.

The above General Preparation Method 4 includes a method of condensing acompound (33) with a heterocyclic compound (34a) in Step 7-1 to preparea compound of the general formula (I-4), the general formula (I-7) orthe general formula (I-8); and a method of condensing a compound (33)with a heterocyclic compound (34b) having a protecting group in Step 7-2to convert the compound (33) into a compound of the general formula(I-5) having a protecting group and then deprotecting the protectinggroup of the compound of the general formula (I-5) and subsequentlyreacting the compound with a compound (2b) in Step 5-3 to prepare acompound of the general formula (I-4), the general formula (I-7) or thegeneral formula (I-8).

[Preparation of Compound of General Formula (I-4) and Compound ofGeneral Formula (I-5)]

The compound of the general formula (I-4) or the compound of the generalformula (I-5) can be prepared by reacting a compound (33) with acompound (34a) or compound (34b) according to Step 7-1 or Step 7-2.Specifically, Step 7-1 or Step 7-2 varies according to the startingmaterial and is not particularly limited insofar as the conditions aresimilar to those in this reaction. A known method described in manydocuments may be used for the reaction. Preferable examples of themethod include Mizoroki-Heck reaction (see R. F. Heck, “Org.Reactions.”, 1982, vol. 27, p. 345, for example), Suzuki-Miyaurareaction (see A. Suzuki, “Chem. Rev.”, 1995, vol. 95, p. 2457, forexample), Sonogashira reaction (see K. Sonogashira, “ComprehensiveOrganic Synthesis”, 1991, vol. 3, p. 521) and Stille coupling reaction(see J. K. Stille, “Angew. Chem. Int. Ed. Engl.”, 1986, vol. 25, p. 508,for example).

In Mizoroki-Heck reaction, a compound (33), wherein L₇′ represents ahydrogen atom and X₁ represents an alkenyl group, and 0.5 to 5.0equivalents of a compound (34a) or compound (34b), wherein L₇ representsa chlorine atom, a bromine atom, an iodine atom or a sulfonate groupsuch as a trifluoromethanesulfonate group, with respect to the compound(33) are stirred in a solvent in the presence of 0.01 to 1.0 equivalentof a transition metal catalyst with respect to the compound (33), forexample. The transition metal catalyst used is preferably a palladiumcomplex, for example, and more preferably a known palladium complex suchas palladium (II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or2-(di-tert-butylphosphino)biphenyl may be preferably added, for example,in order to make the reaction efficiently proceed. A preferable resultmay be achieved in the presence of a base. The base used is notparticularly limited insofar as the base is used in a coupling reactionsimilar to this reaction. Preferable examples of the base includetriethylamine, N,N-diisopropylethylamine, N,N-dicyclohexylmethylamineand tetrabutylammonium chloride. The solvent used varies according tothe starting material and the transition metal catalyst used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Suzuki-Miyaura reaction, a compound (33), wherein L₇′ represents aboronic acid or boronate group, and 0.5 to 5.0 equivalents of a compound(34a) or compound (34b), wherein L₇ represents a chlorine atom, abromine atom, an iodine atom or a sulfonate group such as atrifluoromethanesulfonate group, with respect to the compound (33) arestirred in a solvent in the presence of 0.01 to 1.0 equivalent of atransition metal catalyst with respect to the compound (33), forexample. The transition metal catalyst used is preferably a knownpalladium complex, for example, and more preferably a known palladiumcomplex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine ortri-tert-butylphosphine may be preferably added, for example, in orderto make the reaction efficiently proceed. A good result may be achievedwhen appropriately adding a quaternary ammonium salt, preferablytetrabutylammonium chloride or tetrabutylammonium bromide, for example.In this reaction, a preferable result may be achieved in the presence ofa base. The base used at this time varies according to the startingmaterial, the solvent used and the like, and is not particularlylimited. Preferable examples of the base include sodium hydroxide,barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate,potassium carbonate, cesium carbonate and potassium phosphate. Thesolvent used varies according to the starting material and thetransition metal catalyst used, and is not particularly limited insofaras the solvent does not inhibit the reaction and allows the startingmaterial to be dissolved therein to a certain extent. Preferableexamples of the solvent include acetonitrile, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene,1-methyl-2-pyrrolidone, N,N-dimethylformamide, water and a mixed solventthereof. The reaction temperature must be a temperature that cancomplete the coupling reaction, and is preferably room temperature to200° C., for example. This reaction is performed preferably in an inertgas atmosphere, and more preferably in a nitrogen or argon atmosphere,for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization. The desired compound of the general formula (I-4) orgeneral formula (I-5) can also be obtained from a combination of thecompound (33), wherein L₇′ represents a chlorine atom, a bromine atom,an iodine atom or a sulfonate group such as a trifluoromethanesulfonategroup, with the compound (34a) or compound (34b), wherein L₇ representsa boronic acid or boronate group, by the same method as above.

In Sonogashira reaction, an alkyne compound (33), wherein L₇′ representsa hydrogen atom, and X₁ represents an alkynyl group, and 0.5 to 5equivalents of a compound (34a) or compound (34b), wherein L₇ representsa chlorine atom, a bromine atom, an iodine atom or a sulfonate groupsuch as a trifluoromethanesulfonate group, with respect to the compound(33) are stirred in a solvent in the presence of 0.01 to 1.0 equivalentof a transition metal with respect to the compound (33), for example.The transition metal catalyst used is preferably a known palladiumcomplex, for example, and more preferably a known palladium complex suchas palladium (II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine or tri-tert-butylphosphine maybe preferably added, for example, in order to make the reactionefficiently proceed. In the reaction, a good result may be achieved whenadding a metal halide or a quaternary ammonium salt such as preferablycopper (I) iodide, lithium chloride, tetrabutylammonium fluoride orsilver (I) oxide, for example. A preferable result may be achieved inthe presence of a base. The base used here is not particularly limitedinsofar as the base is used in a coupling reaction similar to thisreaction. Preferable examples of the base include diethylamine,triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.Preferable examples of the solvent used include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethylsulfoxide and a mixture thereof. More preferable examples of the solventinclude tetrahydrofuran, 1,4-dioxane, 1-methyl-2-pyrrolidone andN,N-dimethylformamide. The reaction temperature must be a temperaturethat can complete the coupling reaction, and is preferably roomtemperature to 150° C., for example. This reaction is performedpreferably in an inert gas atmosphere, and more preferably in a nitrogenor argon atmosphere, for example. Under preferable reaction conditions,the reaction is completed in 1 to 24 hours, and the progress of thereaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization.

In Stille coupling reaction, a compound (33), wherein L₇′ represents achlorine atom, a bromine atom, an iodine atom or atrifluoromethanesulfonate group, and 0.5 to 5 equivalents of a compound(34a) or compound (34b), wherein L₇ represents an alkyltin group, withrespect to the compound (33) are stirred in a solvent in the presence of0.01 to 1.0 equivalent of a transition metal catalyst with respect tothe compound (33), for example. The transition metal catalyst used ispreferably a known palladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0), for example, and morepreferably tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0), for example. In order to makethe reaction efficiently proceed, 0.1 to 5.0 equivalents of copper (I)halide or/and lithium chloride may be appropriately used. Preferableexamples of the solvent used include toluene, xylene,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,dimethyl sulfoxide and a mixture thereof. The reaction temperature mustbe a temperature that can complete the coupling reaction, and ispreferably room temperature to 150° C., for example. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere, for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization. The desired compound of the generalformula (I-4) or general formula (I-5) can also be obtained from acombination of the compound (33), wherein L₇′ represents a trialkyltingroup, with the compound (34a) or compound (35b), wherein L₇ representsa chlorine atom, a bromine atom, an iodine atom or atrifluoromethanesulfonate group, by the same method as above.

[Preparation of Compound (34a) and Compound (34b)]

The compound (34a) or compound (34b) can be prepared by the same methodas in the case of the compound (31).

[Preparation of Compound (33)]

The compound (33) can be prepared from a compound (13) or compound (15)by the same method as in Step 2-7 or Step 2-9.

The compound of the general formula (I-7) or the general formula (I-8)can be prepared from the compound (34a) or compound (34b), wherein twoof R¹⁰, R¹¹ and R¹² form a ring, as a starting material by the samemethod as above.

[General Preparation Method 5]

Typically used General Preparation Method 5 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-4, III-5,III-7 or III-8):

is a partial structure corresponding to the above-described Het, whereinAr₁, Ar₂, X₁, X₅, X₆, Y₁₀, Y₁₁, R₁, R₂, R¹⁰, R¹¹, R¹², L₂, Pr, nd, ne,ni and nj are as defined above; and L₈ represents a phosphite group suchas a diethylphosphonyl group, a phosphonium salt such astriphenylphosphonium bromide or a silyl group such as a trimethylsilylgroup.

The above General Preparation Method 5 is an example of a method ofcondensing a compound (35) with a heterocyclic compound (36a) in Step8-1 to prepare a compound of the general formula (I-4), the generalformula (I-7) or the general formula (I-8); or a method of reacting acompound (35) with a heterocyclic compound (36b) having a protectinggroup in Step 8-2 to once convert the compound (35) into a compound ofthe general formula (I-5) having a protecting group and thendeprotecting the protecting group of the compound of the general formula(I-5) and subsequently reacting the compound with a compound (2b) inStep 5-3 to prepare a compound of the general formula (I-4), the generalformula (I-7) or the general formula (I-8).

[Preparation of Compound of General Formula (I-4) and compound ofGeneral Formula (I-5)]

The compound of the general formula (I-4) or the compound of the generalformula (I-5) can be prepared by reacting a compound (35) with acompound (36a) or (36b) according to Step 8-1 or Step 8-2. Specifically,Step 8-1 or Step 8-2 varies according to the starting material and isnot particularly limited insofar as the conditions are similar to thosein this reaction. A known method described in many documents such asWittig reaction, Horner-Emmons reaction or Peterson reaction (see ShinJikken Kagaku Koza (new Courses in Experimental Chemistry), vol. 19,Yuki Gosei (Organic Synthesis) [I], edited by The Chemical Society ofJapan, Maruzen Co., Ltd., June 1992, p. 57-85, for example) may be used.

In Wittig reaction, a compound (35), wherein L₈ represents a phosphoniumsalt, and 0.5 to 2.0 equivalents of a carbonyl compound (36a) or acompound (36b) with respect to the compound (35) are stirred in asolvent in the presence of 1.0 to 5.0 equivalents of a base with respectto the compound (35), for example. This reaction may be a method offirst reacting a compound (35) with a base to form a phosphorus ylideand then adding a carbonyl compound (36a) or a compound (36b) to theylide; or a method of adding a base in the presence of a compound (35)and a carbonyl compound (36a) or a compound (36b). The base used variesaccording to the starting material and the solvent and is notparticularly limited. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; and alkalimetal hydrides such as sodium hydride. The solvent used varies accordingto the starting material and the base used, and is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent used include polar solvents such asnitromethane, acetonitrile, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solventssuch as benzene, toluene and xylene; alcohol solvents such as ethanoland methanol; halogenated solvents such as chloroform and methylenechloride; water; and a mixed solvent thereof. The reaction temperaturemust be a temperature that can complete the reaction without promotingformation of an undesirable by-product, and is preferably −78 to 150°C., for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

In Horner-Emmons reaction, a compound (35), wherein L₈ represents aphosphite group, is reacted with 0.5 to 2.0 equivalents of a carbonylcompound (36a) or a compound (36b) with respect to the compound (35) ina solvent in the presence of 1.0 to 5.0 equivalents of a base withrespect to the compound (35), for example. This reaction may be a methodof first treating a compound (35) and a base to form a carbanion andthen adding a carbonyl compound (36a) or a compound (36b) to thecarbanion; or a method of adding a base in the presence of a compound(35) and a carbonyl compound (36a) or a compound (36b). The base usedvaries according to the starting material and the solvent and is notparticularly limited. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; alkali metalhydrides such as sodium hydride; and alkali metal ammonium salts such assodium amide. The solvent used varies according to the starting materialand the base used, and is not particularly limited insofar as thesolvent does not inhibit the reaction and allows the starting materialto be dissolved therein to a certain extent. Preferable examples of thesolvent include polar solvents such as 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solventssuch as benzene, toluene and xylene; alcohol solvents such as ethanoland methanol; water; and a mixed solvent thereof. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferably −78to 150° C., for example. Under preferable reaction conditions, thereaction is completed in 1 to 24 hours, and the progress of the reactioncan be monitored by a known chromatography technique. An undesirableby-product can be removed by a technique known to a person skilled inthe art such as a conventional chromatography technique, extractionor/and crystallization.

In Peterson reaction, a compound (35), wherein L₈ represents a silylgroup, is reacted with 0.5 to 2.0 equivalents of a carbonyl compound(36a) or a compound (36b) with respect to the compound (35) in a solventin the presence of 1.0 to 5.0 equivalents of a base with respect to thecompound (35), for example. This reaction may be a method of firsttreating a compound (35) and a base to form a carbanion and then addinga carbonyl compound (36a) or a compound (36b) to the carbanion; or amethod of adding a base in the presence of a compound (35) and acarbonyl compound (36a) or a compound (36b). The base used variesaccording to the starting material and the solvent and is notparticularly limited. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; alkali metalhydrides such as sodium hydride; and alkali metal ammonium salts such assodium amide. The solvent used varies according to the starting materialand the base used, and is not particularly limited insofar as thesolvent does not inhibit the reaction and allows the starting materialto be dissolved therein to a certain extent. Preferable examples of thesolvent include polar solvents such as 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solventssuch as benzene, toluene and xylene; alcohol solvents such as ethanoland methanol; water; and a mixed solvent thereof. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferably −78to 150° C., for example. Under preferable reaction conditions, thereaction is completed in 1 to 24 hours, and the progress of the reactioncan be monitored by a known chromatography technique. An undesirableby-product can be removed by a technique known to a person skilled inthe art such as a conventional chromatography technique, extractionor/and crystallization.

[Preparation of Compound (36a) and Compound (36b)]

The compound (36a) and the compound (36b) are commercially available orcan be prepared by a technique known to a person skilled in the art. Ifnot commercially available, the compounds can be prepared by acylationof a compound (31), for example (see Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol. 21, Yuki Gosei (OrganicSynthesis) [III], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., February 1991, p. 184-194, for example).

[Preparation of Compound (35)]

The compound (35) can be prepared from a compound (6) or compound (17)as a starting material by a known method described in many documents.Preferably, for example, i) the compound (35) as a Wittig reagent,wherein L₈ represents a phosphonium salt, can be prepared byhalogenating a corresponding alcohol compound by a method known to aperson skilled in the art (see Shin Jikken Kagaku Koza (New Courses inExperimental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis) [I],edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992,p. 430-438, for example), and then reacting the compound with anorganophosphorus compound such as triphenylphosphine (see OrganicReaction, 1965, vol. 14, p. 270, for example). ii) The compound (35) asa Horner-Emmons reagent, wherein L₈ represents a phosphite, can beprepared by halogenating a corresponding alcohol compound by a methodknown to a person skilled in the art (see Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol. 19, Yuki Gosei (OrganicSynthesis) [I], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., June 1992, p. 430-438, for example), and then reacting thecompound with an alkyl phosphinite by Arbuzov reaction (see ChemicalReview, 1981, vol. 81, p. 415, for example) or with a metal phosphoniteby Becker reaction (see Journal of the American Chemical Society, 1945,vol. 67, p. 1180, for example). Alternatively, the Horner-Emmons reagentcan be prepared from a corresponding carbonyl compound and achlorophosphate in the presence of a base (see The Journal of OrganicChemistry, 1989, vol. 54, p. 4750, for example). iii) The compound (35)as a Peterson reagent, wherein L₉ represents a silyl group, can beprepared from a corresponding halogen compound and a trialkylsilylchloride in the presence of a base (see Journal of OrganometallicChemistry, 1983, vol. 248, p. 51, for example).

The compound of the general formula (I-7) or the compound of the generalformula (I-8) can be prepared from the compound (36a) or compound (36b),wherein two of R¹⁰, R¹¹ and R¹² form a ring, as a starting material bythe same method as above.

[General Preparation Method 6]

Typically used General Preparation Method 6 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-4, III-5,III-7 or III-8):

is a partial structure corresponding to the above-described Het, whereinAr₁, Ar₂, X₁, X₅, X₆, Y₁₀, Y₁₁, R₁, R₂, R¹⁰, R¹¹, R¹², L₂, L₈, Pr, nd,ne, ni and nj are as defined above.

The above General Preparation Method 6 is an example of a method ofcondensing a compound (6) with a heterocyclic compound (38a) in Step 9-1to prepare a compound of the general formula (I-4), the general formula(I-7) or the general formula (I-8); or a method of condensing a compound(6) with a heterocyclic compound (36b) having a protecting group in Step8-2 to once convert the compound (6) into a compound of the generalformula (I-5) having a protecting group and then deprotecting theprotecting group of the compound of the general formula (I-5) andsubsequently reacting the compound with a compound (2b) in Step 5-3 toprepare a compound of the general formula (I-4), the general formula(I-7) or the general formula (I-8).

[Preparation of Compound of General Formula (I-4) and Compound ofGeneral Formula (I-5)]

The compound of the general formula (I-4) or general formula (I-5) canbe prepared by reacting a compound (6) with a compound (38a) or compound(36b) according to Step 9-1 or Step 9-2. Specifically, Step 9-1 or Step9-2 varies according to the starting material and is not particularlylimited insofar as the conditions are similar to those in this reaction.A known method described in many documents such as Wittig reaction,Horner-Emmons reaction or Peterson reaction may be used for the reaction(see Jikken Kagaku Koza (Courses in Experimental Chemistry), vol. 19,Yuki Gosei (Organic Synthesis) [I], edited by The Chemical Society ofJapan, Maruzen Co., Ltd., June 1992, p. 57-85, for example).

In Wittig reaction, a carbonyl compound (6) and 0.5 to 2.0 equivalentsof a compound (38a) or compound (38b), wherein L₈ represents aphosphonium salt, with respect to the carbonyl compound (6) are stirredin a solvent in the presence of 1.0 to 5.0 equivalents of a base withrespect to the carbonyl compound (6), for example. This reaction may bea method of first reacting a compound (38a) or compound (38b) with abase to form a phosphorus ylide and then adding a carbonyl compound (6)to the ylide; or a method of adding a base in the presence of a carbonylcompound (6) and a compound (38a) or compound (38b). The base usedvaries according to the starting material and the solvent and is notparticularly limited. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; and alkalimetal hydrides such as sodium hydride. The solvent used varies accordingto the starting material and the base used, and is not particularlylimited insofar as the solvent does not inhibit the reaction and allowsthe starting material to be dissolved therein to a certain extent.Preferable examples of the solvent used include polar solvents such asnitromethane, acetonitrile, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solventssuch as benzene, toluene and xylene; alcohol solvents such as ethanoland methanol; halogenated solvents such as chloroform and methylenechloride; water; and a mixed solvent thereof. The reaction temperaturemust be a temperature that can complete the reaction without promotingformation of an undesirable by-product, and is preferably −78 to 150°C., for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

In Horner-Emmons reaction, a carbonyl compound (6) and 0.5 to 2.0equivalents of a compound (38a) or compound (38b), wherein L₈ representsa phosphite group, with respect to the carbonyl compound (6) are stirredin a solvent in the presence of 1.0 to 5.0 equivalents of a base withrespect to the carbonyl compound (6), for example. This reaction may bea method of first treating a compound (38a) or compound (38b) and a baseto form a carbanion and then adding a carbonyl compound (6) to thecarbanion; or a method of adding a base in the presence of a carbonylcompound (6) and a compound (38a) or compound (38b). The base usedvaries according to the starting material and the solvent and is notparticularly limited. Preferable examples of the base include alkalimetal hydroxides such as sodium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate; alkali metal salts ofalcohols such as sodium methoxide and potassium tert-butoxide; organicbases such as triethylamine, pyridine and diazabicyclononene; organicmetals such as butyl lithium and lithium diisobutylamide; alkali metalhydrides such as sodium hydride; and alkali metal ammonium salts such assodium amide. The solvent used varies according to the starting materialand the base used, and is not particularly limited insofar as thesolvent does not inhibit the reaction and allows the starting materialto be dissolved therein to a certain extent. Preferable examples of thesolvent include polar solvents such as 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such astetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solventssuch as benzene, toluene and xylene; alcohol solvents such as ethanoland methanol; water; and a mixed solvent thereof. The reactiontemperature must be a temperature that can complete the reaction withoutpromoting formation of an undesirable by-product, and is preferably −78to 150° C., for example. Under preferable reaction conditions, thereaction is completed in 1 to 24 hours, and the progress of the reactioncan be monitored by a known chromatography technique. An undesirableby-product can be removed by a technique known to a person skilled inthe art such as a conventional chromatography technique, extractionor/and crystallization.

In Peterson reaction, a carbonyl compound (6) and 0.5 to 2.0 equivalentsof a compound (38a) or compound (38b), wherein L₈ represents a silylgroup, with respect to the carbonyl compound (6) are stirred in asolvent in the presence of 1.0 to 5.0 equivalents of a base with respectto the carbonyl compound (6), for example. This reaction may be a methodof first treating a compound (38a) or compound (38b) and a base to forma carbanion and then adding a carbonyl compound (6) to the carbanion; ora method of adding a base in the presence of a carbonyl compound (6) anda compound (38a) or compound (38b). The base used varies according tothe starting material and the solvent and is not particularly limited.Preferable examples of the base include alkali metal hydroxides such assodium hydroxide and lithium hydroxide; alkali metal carbonates such assodium carbonate; alkali metal salts of alcohols such as sodiummethoxide and potassium tert-butoxide; organic bases such astriethylamine, pyridine and diazabicyclononene; organic metals such asbutyl lithium and lithium diisobutylamide; alkali metal hydrides such assodium hydride; and alkali metal ammonium salts such as sodium amide.The solvent used varies according to the starting material and the baseused, and is not particularly limited insofar as the solvent does notinhibit the reaction and allows the starting material to be dissolvedtherein to a certain extent. Preferable examples of the solvent includepolar solvents such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide anddimethyl sulfoxide; ether solvents such as tetrahydrofuran, 1,4-dioxaneand 1,2-dimethoxyethane; nonpolar solvents such as benzene, toluene andxylene; alcohol solvents such as ethanol and methanol; water; and amixed solvent thereof. The reaction temperature must be a temperaturethat can complete the reaction without promoting formation of anundesirable by-product, and is preferably −78 to 150° C., for example.Under preferable reaction conditions, the reaction is completed in 1 to24 hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

[Preparation of Compound (38a) and Compound (38b)]

The compound (38a) and the compound (38b) are commercially available orprepared by a technique known to a person skilled in the art. If notcommercially available, for example, i) the compound (38a) or compound(38b) as a Wittig reagent, wherein L₈ represents a phosphonium salt, canbe prepared by halogenating a corresponding alcohol compound by a methodknown to a person skilled in the art (see Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol. 19, Yuki Gosei (OrganicSynthesis) [I], edited by The Chemical Society of Japan, Maruzen Co.,Ltd., June 1992, p. 430-438, for example), and then reacting thecompound with an organophosphorus compound such as triphenylphosphine(see Organic Reaction, 1965, vol. 14, p. 270, for example). ii) Thecompound (38a) or compound (38b) as a Horner-Emmons reagent, wherein L₈represents a phosphite, can be prepared by halogenating a correspondingalcohol compound by a method known to a person skilled in the art (seeShin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [I], edited by The Chemical Societyof Japan, Maruzen Co., Ltd., June 1992, p. 430-438, for example), andthen reacting the compound with an alkyl phosphinite by Arbuzov reaction(see Chemical Review, 1981, vol. 81, p. 415, for example) or with ametal phosphonite by Becker reaction (see Journal of the AmericanChemical Society, 1945, vol. 67, p. 1180, for example). Alternatively,the compound can be prepared from a corresponding carbonyl compound anda chlorophosphate in the presence of a base (see Journal of OrganicChemistry, 1989, vol. 54, p. 4750, for example). iii) The compound (38a)or compound (38b) as a Peterson reagent, wherein L₉ represents a silylgroup, can be prepared from a corresponding halogen compound and atrialkylsilyl chloride (see Journal of Organometallic Chemistry, 1983,vol. 248, p. 51, for example).

The compound of the general formula (I-7) or the compound of the generalformula (I-8) can be prepared from the compound (38a) or compound (38b),wherein two of R¹⁰, R¹¹ and R¹² form a ring, as a starting material bythe same method as above.

[General Preparation Method 7]

Typically used General Preparation Method 7 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-4, III-7 orIII-8):

is a partial structure corresponding to the above-described Het,wherein Ar₁, Ar₂, X₁, X₅, X₆, Y₁₀, Y₁₁, R¹⁰, R¹¹, R¹², L₇, L₇′, nd, ne,ni and nj are as defined above; and R¹¹¹ is as defined for R¹¹.

The above General Preparation Method 7 is an example of a method ofcondensing a compound (39) with a compound (40) in Step 10 to prepare acompound of the general formula (I-4), the general formula (I-7) or thegeneral formula (I-8).

[Preparation of Compound of General Formula (I-4)]

The compound of the general formula (I-4) can be prepared by reacting acompound (39) with a compound (40) according to Step 10. Specifically,Step 10 varies according to the starting material and is notparticularly limited insofar as the conditions are similar to those inthis reaction. A known method described in many documents such asMizoroki-Heck reaction (see R. F. Heck, “Org. Reactions.”, 1982, vol.27, p. 345, for example), Suzuki-Miyaura reaction (see A. Suzuki, “Chem.Rev.”, 1995, vol. 95, p. 2457, for example), Sonogashira reaction (seeK. Sonogashira, “Comprehensive Organic Synthesis”, 1991, vol. 3, p. 521)or Stille coupling reaction (see J. K. Stille, “Angew. Chem. Int. Ed.Engl.”, 1986, vol. 25, p. 508, for example) may be used for thereaction.

In Mizoroki-Heck reaction, a compound (39), wherein L₇′ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of analkene compound (40), wherein L₇ represents a hydrogen atom and R¹¹¹represents a C1-6 alkenyl group which may be substituted with 1 to 3substituents selected from the above Substituent Group A1, with respectto the compound (39) are stirred in a solvent in the presence of 0.01 to0.2 equivalent of a transition metal catalyst with respect to thecompound (39), for example. The transition metal catalyst used ispreferably a palladium complex, for example, and more preferably a knownpalladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine or2-(di-tert-butylphosphino)biphenyl may be preferably added, for example,in order to make the reaction efficiently proceed. A preferable resultmay be obtained in the presence of a base, and the base used is notparticularly limited insofar as the base is used in a coupling reactionthe same as this reaction. Preferable examples of the base includetriethylamine, N,N-diisopropylethylamine, N,N-dicyclohexylmethylamineand tetrabutylammonium chloride. The solvent used varies according tothe starting material and the transition metal catalyst used, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Suzuki-Miyaura reaction, a compound (39), wherein L₇′ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 10.0 equivalents of acompound (40), wherein L₇ represents a boronic acid group or a boronategroup, with respect to the compound (39) are stirred in a solvent in thepresence of 0.01 to 0.5 equivalent of a transition metal catalyst withrespect to the compound (39), for example. The transition metal catalystused is preferably a known palladium complex, and more preferably aknown palladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine ortri-tert-butylphosphine may be preferably added, for example, in orderto make the reaction efficiently proceed. A quaternary ammonium salt,preferably tetrabutylammonium chloride or tetrabutylammonium bromide,for example, may also be added in order to make the reaction efficientlyproceed. In this reaction, a preferable result may be achieved in thepresence of a base. The base used at this time varies according to thestarting material, the solvent used and the like, and is notparticularly limited. Preferable examples of the base include sodiumhydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodiumcarbonate, potassium carbonate, cesium carbonate and potassiumphosphate. The solvent used varies according to the starting materialand the transition metal catalyst used, and is not particularly limitedinsofar as the solvent does not inhibit the reaction and allows thestarting material to be dissolved therein to a certain extent.Preferable examples of the solvent include acetonitrile,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide, water and a mixedsolvent thereof. The reaction temperature must be a temperature that cancomplete the coupling reaction, and is preferably room temperature to200° C., for example. This reaction is performed preferably in an inertgas atmosphere, and more preferably in a nitrogen or argon atmosphere,for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization. The desired compound of the general formula (I-4) canalso be obtained from a combination of the compound (39), wherein L₇′represents a boronic acid group or a boronate group, with the compound(40), wherein L₇ represents a chlorine atom, a bromine atom, an iodineatom or a sulfonate group such as a trifluoromethanesulfonate group, bythe same method as above.

In Sonogashira reaction, a compound (39), wherein L₇′ represents achlorine atom, a bromine atom, an iodine atom or a sulfonate group suchas a trifluoromethanesulfonate group, and 1.0 to 10 equivalents of analkyne compound (40), wherein L₇ represents a hydrogen atom and R¹¹¹represents a C1-6 alkynyl group which may be substituted with 1 to 3substituents selected from the above Substituent Group A1, with respectto the compound (39) are stirred in a solvent in the presence of 0.01 to0.5 equivalent of a transition metal catalyst with respect to thecompound (39), for example. The transition metal catalyst used ispreferably a known palladium complex, for example, and more preferably aknown palladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such astriphenylphosphine, tri-o-tolylphosphine or tri-tert-butylphosphine maybe preferably added, for example, in order to make the reactionefficiently proceed. In the reaction, a good result may be achieved whenadding a metal halide or a quaternary ammonium salt, preferably copper(I) iodide, lithium chloride, tetrabutylammonium fluoride or silver (I)oxide, for example. A preferable result may be obtained in the presenceof a base, and the base used here is not particularly limited insofar asthe base is used in a coupling reaction the same as this reaction.Preferable examples of the base include diethylamine, triethylamine,N,N-diisopropylethylamine, piperidine and pyridine. Preferable examplesof the solvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone,N,N-dimethylformamide and dimethyl sulfoxide. More preferable examplesof the solvent include tetrahydrofuran, 1,4-dioxane,1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reactiontemperature must be a temperature that can complete the couplingreaction, and is preferably room temperature to 150° C., for example.This reaction is performed preferably in an inert gas atmosphere, andmore preferably in a nitrogen or argon atmosphere, for example. Underpreferable reaction conditions, the reaction is completed in 1 to 24hours, and the progress of the reaction can be monitored by a knownchromatography technique. An undesirable by-product can be removed by atechnique known to a person skilled in the art such as a conventionalchromatography technique, extraction or/and crystallization.

In Stille coupling reaction, a compound (39), wherein L₇′ represents achlorine atom, a bromine atom, an iodine atom or atrifluoromethanesulfonate group, and 1.0 equivalent or more of acompound (40), wherein L₇ represents a trialkyltin group, with respectto the compound (39) are stirred in a solvent in the presence of 0.01 to0.2 equivalent of a transition metal catalyst with respect to thecompound (39), for example. The transition metal catalyst used ispreferably a palladium complex, for example, and more preferably a knownpalladium complex such as palladium (II) acetate,dichlorobis(triphenylphosphine)palladium (II),tetrakis(triphenylphosphine)palladium (0) ortris(dibenzylideneacetone)dipalladium (0). In order to make the reactionefficiently proceed, 0.1 to 5.0 equivalents of copper (I) halide or/andlithium chloride may be added. Preferable examples of the solvent usedinclude toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone and dimethyl sulfoxide. The reaction temperaturemust be a temperature that can complete the coupling reaction, and ispreferably room temperature to 150° C., for example. This reaction isperformed preferably in an inert gas atmosphere, and more preferably ina nitrogen or argon atmosphere, for example. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization. The desired compound of the generalformula (I-4) can also be obtained from a combination of the compound(39), wherein L₇′ represents a trialkyltin group, with the compound(40), wherein L₇ represents a chlorine atom, a bromine atom, an iodineatom or a trifluoromethanesulfonate group, by the same method as above.The compound (40) is commercially available or can be prepared by amethod known to a person skilled in the art.

[Preparation of Compound (39)]

The compound (39) can be prepared by a method in the above GeneralPreparation Methods 1 to 6.

The compound of the general formula (I-7) or the general formula (I-8)can be prepared by the same method as above using, as a startingmaterial, the compound (39), wherein R¹⁰ and R¹² each represent an alkylgroup substituted with an alkenyl group or an alkynyl group or analkenyl group, an alkynyl group or an alkyl group substituted with ahalogen atom and L₇′ represents a chlorine atom, a bromine atom, aniodine atom, a sulfonate group such as a trifluoromethanesulfonategroup, or a trialkyltin group, without use of the compound (40).

[General Preparation Method 8]

Typically used General Preparation Method 8 for the compound of thegeneral formula (I) of the present invention will be described below.

In the formula, the following partial structure (formula III-4, III-7 orIII-8):

is a partial structure corresponding to the above-described Het,wherein Ar₁, Ar₂, X₁, X₅, X₆, Y₁₀, Y₁₁, R¹⁰, R¹¹, R¹², L₃, nd, ne, niand nj are as defined above.

The above General Preparation Method 8 is an example of a method ofcondensing a compound (41) with a compound (42) in Step 12 to prepare acompound of the general formula (I-4), the general formula (I-7) or thegeneral formula (I-8).

[Preparation of Compound of General Formula (I-4)]

The compound of the general formula (I-4) can be prepared by condensinga compound (41) with a compound (42) according to Step 12. Specifically,Step 12 varies according to the starting material and is notparticularly limited insofar as the conditions are similar to those inthis reaction. For example, a known method described in many documentssuch as coupling reaction using a copper compound of an arylboronic acidderivative (see The Journal of Organic Chemistry, 2001, vol. 66, p.7892, for example), Ullmann reaction (see Journal of MedicinalChemistry, 1981, vol. 24, p. 1139, for example) or nucleophilicsubstitution reaction (see Journal of Medicinal Chemistry, 1991, vol.39, p. 2671-2677, for example) may be used for the reaction.

The coupling reaction of an arylboronic acid derivative using a coppercompound is, for example, a method of stirring a compound (41), whereinL₃ represents a boronic acid group or a boronate group, and 1.0 to 10.0equivalents of a compound (42) with respect to the compound (41) in asolvent in the presence of 0.01 to 1.0 equivalent of a copper reagentsuch as copper, copper bromide or copper iodide with respect to thecompound (41) by addition of 1.0 to 10.0 equivalents of a base withrespect to the compound (41). The base used varies according to thestarting material, the solvent used and the like, and is notparticularly limited insofar as the base does not inhibit the reaction.Preferable examples of the base include organic bases such astriethylamine, pyridine and tetramethylethylenediamine; alkali metalsalts such as potassium carbonate, sodium carbonate, potassium acetate,sodium acetate and cesium carbonate; and metal alkoxides such as sodiummethoxide and potassium tert-butoxide. The copper reagent used variesaccording to the starting material and is not particularly limited.Preferable examples of the copper reagent include copper acetate anddi-μ-hydroxo-bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)]chloride. The solvent used varies according to the startingmaterial, the reagent and the like, and is not particularly limitedinsofar as the solvent does not inhibit the reaction and allows thestarting material to be dissolved therein to a certain extent.Preferable examples of the solvent include ether solvents such astetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated solventssuch as methylene chloride, 1,2-dichloroethane and chloroform; polarsolvents such as ethyl acetate, N,N-dimethylformamide andN-methylpyrrolidone; nonpolar solvents such as toluene, benzene anddichlorobenzene; and a mixture thereof. The reaction temperature must bea temperature that can complete the reaction without promoting formationof an undesirable by-product, and is preferably room temperature to 200°C., for example. Good results such as reduction in the reaction time andimprovement of the yield may be achieved when the reaction is performedin an oxygen atmosphere or air stream. Under preferable reactionconditions, the reaction is completed in 1 to 24 hours, and the progressof the reaction can be monitored by a known chromatography technique. Anundesirable by-product can be removed by a technique known to a personskilled in the art such as a conventional chromatography technique,extraction or/and crystallization.

In Ullmann reaction, a compound (41), wherein L₃ represents a halogenatom such as a chlorine atom, a bromine atom or an iodine atom, and 1.0to 10.0 equivalents of a compound (42) with respect to the compound (41)are stirred in a solvent in the presence of 0.01 to 1.0 equivalent of acopper reagent such as copper, copper bromide or copper iodide withrespect to the compound (41) by addition of 1.0 to 10.0 equivalents of abase with respect to the compound (41), for example. The base usedvaries according to the starting material and is not particularlylimited. Preferable examples of the base include alkali metal salts suchas potassium carbonate, sodium carbonate, potassium acetate, sodiumacetate and cesium carbonate; and metal alkoxides such as sodiummethoxide and potassium tert-butoxide. The solvent used varies accordingto the starting material, the reagent and the like, and is notparticularly limited insofar as the solvent does not inhibit thereaction and allows the starting material to be dissolved therein to acertain extent. Preferable examples of the solvent that can be usedinclude ether solvents such as tetrahydrofuran, 1,4-dioxane and diethylether; halogenated solvents such as methylene chloride,1,2-dichloroethane and chloroform; alcohol solvents such as amyl alcoholand isopropyl alcohol; polar solvents such as N,N-dimethylformamide andN-methylpyrrolidone; nonpolar solvents such as toluene, benzene anddichlorobenzene; and a mixture thereof. The reaction temperature must bea temperature that can complete the reaction without promoting formationof an undesirable by-product, and is preferably room temperature to 200°C., for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique, extraction or/andcrystallization.

In nucleophilic substitution reaction, a compound (41), wherein L₃represents a halogen atom such as a chlorine atom, a bromine atom or aniodine atom or a sulfonate group such as a methanesulfonate group, ap-toluenesulfonate group or a trifluoromethanesulfonate group, and 2.0to 5.0 equivalents of a compound (42) with respect to the compound (41)are stirred in a solvent in the presence or absence of 1.0 to 5.0equivalents of a base with respect to the compound (41), for example.The base used varies according to the starting material and is notparticularly limited. Preferable examples of the base include sodiumhydride, sodium hydroxide, potassium hydroxide, potassium carbonate,sodium carbonate, cesium carbonate, barium carbonate, pyridine, lutidineand triethylamine. The solvent used varies according to the startingmaterial, and is not particularly limited insofar as the solvent doesnot inhibit the reaction and allows the starting material to bedissolved therein to a certain extent. Preferable examples of thesolvent include acetonitrile, tetrahydrofuran, dimethyl sulfoxide,N,N-dimethylformamide and N-methylpyrrolidine. The base may optionallybe used as a solvent. The reaction temperature must be a temperaturethat can complete the reaction without promoting formation of anundesirable by-product, and is preferably room temperature to 150° C.,for example. Under preferable reaction conditions, the reaction iscompleted in 1 to 24 hours, and the progress of the reaction can bemonitored by a known chromatography technique. An undesirable by-productcan be removed by a technique known to a person skilled in the art suchas a conventional chromatography technique or/and crystallization.

[Preparation of Compound (41)]

The compound (41) is prepared by the same method as in the above GeneralPreparation Methods 1 to 7.

[Preparation of Compound (42)]

The compound (42) is commercially available or prepared by a methodknown to a person skilled in the art.

The compound of the general formula (I-7) or the general formula (I-8)can be prepared from the compound (41), wherein two of R¹⁰, R¹¹ and R¹²form a ring, as a starting material by the same method as above.

General Preparation Methods 1 to 8 for the compound of the presentinvention described above in detail are methods for preparing a compoundrepresented by the general formula (I-9), the general formula (I-4), thegeneral formula (I-5), the general formula (I-6), the general formula(I-7) or the general formula (I-8), wherein Het falls within a part ofthe definition of Het in the general formula (I). However, the compoundof the general formula (I), wherein Het falls within another part of thedefinition of Het, can be prepared almost in the same manner as in theabove General Preparation Methods 1 to 8, or can be prepared by anothermethod itself known to a person skilled in the art. The examplesdescribed later will provide reference to these Preparation Methods, andthe compound of the general formula (I) can be easily prepared by amethod itself known to a person skilled in the art based on theseexamples.

The compound of the general formula (I) or pharmacologically acceptablesalt thereof according to the present invention is effective forprevention or treatment of a disease caused by Aβ and is excellent interms of pharmacokinetics, toxicity, stability, absorption and the like.

A prophylactic or therapeutic agent for a disease caused by Aβcomprising the compound of the formula (I) or pharmacologicallyacceptable salt thereof according to the present invention as an activeingredient can be prepared by a conventional method. Preferable examplesof the dosage form include tablets, powders, fine granules, granules,coated tablets, capsules, syrups, troches, inhalants, suppositories,injections, ointments, ophthalmic solutions, ophthalmic ointments, nasaldrops, ear drops, cataplasms and lotions. The prophylactic ortherapeutic agent can be prepared by using ingredients typically usedsuch as an excipient, a binder, a lubricant, a colorant and acorrective, and ingredients used where necessary such as a stabilizer,an emulsifier, an absorbefacient, a surfactant, a pH adjuster, apreservative and an antioxidant, and can be prepared by blendingingredients generally used as materials for a pharmaceuticalpreparation. Examples of such ingredients include animal and vegetableoils such as soybean oil, beef tallow and synthetic glyceride;hydrocarbons such as liquid paraffin, squalane and solid paraffin; esteroils such as octyldodecyl myristate and isopropyl myristate; higheralcohols such as cetostearyl alcohol and behenyl alcohol; a siliconeresin; silicone oil; surfactants such as polyoxyethylene fatty acidester, sorbitan fatty acid ester, glycerin fatty acid ester,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenatedcastor oil and a polyoxyethylene-polyoxypropylene block copolymer;water-soluble polymers such as hydroxyethylcellulose, polyacrytic acid,a carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone andmethylcellulose; lower alcohols such as ethanol and isopropanol;polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and sucrose; inorganicpowders such as silicic anhydride, magnesium aluminum silicate andaluminum silicate; and purified water. Examples of the excipient usedinclude lactose, corn starch, saccharose, glucose, mannitol, sorbitol,crystalline cellulose and silicon dioxide. Examples of the binder usedinclude polyvinyl alcohol, polyvinyl ether, methylcellulose,ethylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylmethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene blockcopolymer and meglumine. Examples of the disintegrator used includestarch, agar, gelatin powder, crystalline cellulose, calcium carbonate,sodium bicarbonate, calcium citrate, dextrin, pectin andcarboxymethylcellulose calcium. Examples of the lubricant used includemagnesium stearate, talc, polyethylene glycol, silica and hydrogenatedvegetable oil. Examples of the colorant used include those permitted tobe added to pharmaceuticals. Examples of the corrective used includecocoa powder, menthol, empasm, mentha oil, borneol and cinnamon powder.

For example, an oral preparation is prepared by adding an activeingredient compound or a salt thereof or a hydrate of the compound orsalt, an excipient, and, where necessary, a binder, a disintegrant, alubricant, a colorant and a corrective, for example, and then formingthe mixture into powder, fine granules, granules, tablets, coatedtablets or capsules, for example, by a conventional method. It isobvious that tablets or granules may be appropriately coated, forexample, sugar coated, where necessary. A syrup or an injectionpreparation is prepared by adding a pH adjuster, a solubilizer and anisotonizing agent, for example, and a solubilizing agent, a stabilizerand the like where necessary by a conventional method. An externalpreparation may be prepared by any conventional method without specificlimitations. As a base material, any of various materials usually usedfor a pharmaceutical, a quasi drug, a cosmetic or the like may be used.Examples of the base material include materials such as animal andvegetable oils, mineral oils, ester oils, waxes, higher alcohols, fattyacids, silicone oils, surfactants, phospholipids, alcohols, polyhydricalcohols, water-soluble polymers, clay minerals and purified water. A pHadjuster, an antioxidant, a chelator, a preservative and fungicide, acolorant, a flavor or the like may be added where necessary. Further, aningredient having a differentiation inducing effect such as a blood flowenhancer, a bactericide, an antiphlogistic, a cell activator, vitamin,amino acid, a humectant or a keratolytic agent may be blended wherenecessary.

The dose of the therapeutic or prophylactic agent of the presentinvention varies according to the degree of symptoms, age, sex, bodyweight, mode of administration, type of salt and specific type ofdisease, for example. Typically, the compound of the formula (I) orpharmacologically acceptable salt thereof is orally administered to anadult at about 30 μg to 10 g, preferably 100 μg to 5 g, and morepreferably 100 μg to 100 mg per day, or is administered to an adult byinjection at about 30 μg to 1 g, preferably 100 μg to 500 mg, and morepreferably 100 μg to 30 mg per day, in a single dose or several divideddoses, respectively.

For prevention or treatment of a disease caused by Aβ such asAlzheimer's disease, senile dementia, Down's disease and amyloidosis,the compound represented by the formula (I) or a pharmacologicallyacceptable salt thereof according to the present invention may be usedin combination with for compounds having mechanisms as described below.

For example, such compounds include cholinesterase inhibitors (e.g.,donepezil, huperzine A, tacrine, rivastigmine, galantamine); AMPAreceptor antagonists (e.g., 1,2-dihydropyridine compounds such as3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one); NMDAreceptor antagonists (e.g., memantine); acetylcholine releasingstimulants (e.g., pramiracetam; aniracetam); calcium channel agonists(e.g., nefiracetam); free radical scavengers (e.g., EGb 761); plateletactivating factor antagonists (e.g., EGb 761); platelet aggregationantagonists (e.g., EGb 761, triflusal); insulin sensitizers (e.g.,rosiglitazone); peroxisome proliferator-activated receptor agonists(e.g., rosiglitazone); peroxisome proliferator-activated receptor gammaagonists (e.g., rosiglitazone); monoamine oxidase B inhibitors (e.g.,rasagiline, selegiline, procaine); carnitine acetyltransferasestimulants (e.g., levacecarnine); NSAIDs (e.g., triflusal,cyclooxygenase-2 inhibitors, such as celecoxib); nerve growth factoragonists (e.g., xaliproden, FPF 1070); beta-amyloid inhibitors (e.g.,tarenflurbil, tramiprosate, leuprorelin-D); immunomodulators (e.g.,tarenflurbil, immune globulin, icosapentethyl ester); NF-kappa Binhibitors (e.g., tarenflurbil); thyrotropin releasing hormone agonists(e.g., taltirelin); dopamine D2 receptor antagonists (e.g.,risperidone); serotonin 2 receptor antagonists (e.g., risperidone);muscarinic M1 receptor agonists (e.g., cevimeline); alpha 1 adrenoceptoragonists (e.g., modafinil); serotonin 3 receptor antagonists (e.g.,alosetron); dopamine D2 receptor agonists (e.g., aripiprazole); dopamineD2 receptor antagonists (e.g., aripiprazole); serotonin 1A receptoragonists (e.g., aripiprazole); serotonin 2A receptor antagonists (e.g.,aripiprazole); glucocorticoid antagonists (e.g., mifepristone);progesterone antagonists (e.g., mifepristone); HMG-CoA reductaseinhibitors (e.g., atorvastatin, simvastatin); adenosine uptakeinhibitors (e.g., propentofylline); phosphodiesterase inhibitors (e.g.,propentofylline); acetylcholine receptor agonists (e.g., cholinealfoscerate); membrane permeability enhancers (e.g., cholinealfoscerate); cannabinoid 1 receptor antagonists (e.g., rimonabant);cannabinoid receptor agonists (e.g,. dronabinol); angiogenesisinhibitors (e.g., paclitaxel); immunosuppressants (e.g., paclitaxel);tubulin antagonists (e.g., paclitaxel); thromboxane A2 synthaseinhibitors (e.g., triflusal); antioxidants (e.g., idebenone); alphaadrenoreceptor antagonists (e.g., nicergoline); estrogen agonists (e.g.,conjugated estrogens, trilostane); 3-beta hydroxysteroid dehydrogenaseinhibitors (e.g., trilostane); signal transduction pathway inhibitors(e.g., trilostane); melatonin receptor agonists (e.g., ramelteon);immunostimulants (e.g., immune globulin, icosapentethyl ester,procaine); HIV entry inhibitors (e.g., procaine); sodium channelantagonists (e.g., procaine); microtubule inhibitor (e.g., CPH 82);glycine NMDA agonists (e.g., cycloserine); adenosine A1 receptorantagonists (e.g., KW 3902); ATPase stimulants (e.g., triacetyluridine);mitochondrial function enhancers (e.g, triacetyluridine); growth hormonereleasing factor agonists (e.g., tesamorelin); butylcholine esteraseinhibitor (e.g., bisnorcymserine); alpha adrenergic receptor antagonists(e.g., nicergoline); NO synthase type II inhibitors (e.g., arundicacid); chelating agents (e.g., PBT 2); amyloid fibrillogenesisinhibitors (e.g., TTP488, PF 4494700); serotonin 4 receptor agonists(e.g., PRX 03140); serotonin 6 receptor antagonists (e.g., SB 742457);benzodiazepine receptor inverse agonists (e.g., radequinil); Ca channelantagonists (e.g., safinamide); nicotinic receptor agonists (e.g.,ispronicline); and ACE inhibitor (e.g., CTS 21166).

Further, the above compounds include, for example, huperzine A, tacrine,rivastigmine, galantamine, pramiracetam, aniracetam, nefiracetam, EGb761, rosiglitazone, rasagiline, levacecarnine, celecoxib,3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one,talampanel, becampanel, memantine, xaliproden, tarenflurbil,tramiprosate, leuprorelin-D, taltirelin, risperidone, cevimeline,modafinil, alosetron, aripiprazole, mifepristone, atorvastatin,propentofylline, choline alfoscerate, FPF 1070 (CAS Number 143637-01-8),rimonabant, dronabinol, docosahexaenoic acid, paclitaxel, triflusal,idebenone, nicergoline, conjugated estrogens, trilostane, simvastatin,selegiline, ramelteon, immune globulin, icosapentethyl ester, procaine,CPH 82, cycloserine, KW 3902 (CAS Number 136199-02-5), triacetyluridine,estrogen dementia therapeutics (e.g., MIGENIX, Vancouver, Canada),tesamorelin, bisnorcymserine, nicergoline, arundic acid, PBT 2, TTP488,PF 4494700, PRX 03140, SB 742457, radequinil, safinamide, ispronicline,CTS 21166, Bapineuzumab, NP 031112,(2S,3aS,7aS)-1{[(R,R)-2-Phenylcyclopropyl]carbonyl}-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole,citalopram, venlafaxine, levprorelin, prasterone, peptide T (CAS Number53-43-0), besipiridine, lexipafant, stacofylline, SGS 742 (CAS Number123690-78-8), T 588 (CAS Number 142935-03-3), nerispiridine,dexanabinol, sabcomeline, GTS 21 (CAS Number 156223-05-1), CX 516 (CASNumber 154235-83-3), ABT 089 (CAS Number 161417-03-4), anapsos,tesofensine, SIB 1553A (i.e.,4-[[2-(1-methyl-yl-2-pyrrolidinyl)ethyl]thia]phenol), ladostigil,radequinil, GPI 1485, ispronicline, arundic acid, MEM 1003 (i.e.,3-Isopropyl 5-(2-methoxyethyl)4-(2-chloro-3-cyanophenyl)-2,6-dimethylpyridine-3,5-dicarboxylate), V3381 (i.e., 2-(2,3-Dihydro-1H-inden-3-ylamino)acetamide hydrochloride),farampator, paliroden, prasterone-paladin, urocortin, DP b99 (i.e.,2,2′-(Ethylenedioxy)bis(2,1-phenylene)bis[N-[2-[2-(octyloxy)ethoxy]-2-oxoethyl]imino]bis(aceticacid)), capserod, DU 125530, bapineuzumab, AL 108 (i.e.,L-Asparaginyl-L-alanyl-L-prolyl-L-valyl-L-seryl-L-isoleucyl-L-prolyl-L-glutamine),DAS 431, DEBIO 9902, DAR 100, mitoquinone, IPL 455903 (i.e.,5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin-2-one),E2CDS, PYM 50028, PBT 2, lecozotan, SB 742457, CX 717, AVE 1625 (i.e.,1-(bis(4-chlorophenyl)methyl)-3-((3,5-difluorophenyl)(methylsulfonyl)methylene)azetidine),LY 450139 (i.e.,N2-[2(s)-Hydroxy-3-methylbutyryl]-N1-[3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1(S)-yl]-L-alaninamide),EM 1421 (i.e.,4,4′-[(2R,3S)-2,3-Dimethylbutane-1,4-diyl]bis(1,2-dimethoxybenzene), SRN001, TTP 488, PRX 03140, dimebolin, glycine-proline-glutamate, C105, AL208, MEM 3454, AC 1202, L 830982, LY 451395 (i.e.,(R)—N-[2-[4-(methylsulfonamidomethyl)biphenyl-4-yl]propyl]propane-2-sulfonamide),MK 0249, LY 2062430, diethylnorspermine, neboglamine, S 18986, SA 4503(CAS Number 165377-44-6), GRI 1, S 17092 (i.e.,(2S,3aS,7aS)-1{[(R,R)-2-Phenylcyclopropyl]carbonyl}-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole),SL 251188, EUK 189, R 1450,6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one,CERE 110, dexefaroxan, CAD 106, HF 0220, HF 0420, EHT 0202, VP 025, MEM1414, BGC 201259 (i.e., N,N-Dimethylcarbamic acid,4-[1(S)-(methylamino)-3-(4-nitrophenoxy)propyl]phenyl ester), EN 100,ABT 834, ABT 239 (i.e.,4-[2-[2-[(2R)-2-Methylpyrrolidinyl]ethyl]-benzofuran-5-yl]benzonitrile),SGS 518, R 1500, C 9138, SSR 180711, alfatradiol, R 1577, T 817MA (i.e.,1-[3-[2-(1-Benzothien-5-yl)ethoxy]propyl]azetidin-3-olmaleate), CNP 1061(i.e., 4-Methyl-5-(2-nitrooxyethyl)thiazole), KTX 0101 (i.e., sodiumbeta-hydroxybutyrate), GSK 189254 (i.e.,6-[3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]-N-methylnicotinamide),AZD 1080, ACC 001, PRX 07034, midazolam, R-phenserine, AZD 103 (CASNumber 488-59-5), SN 522, NGX 267 (CAS Number 503431-81-0), N-PEP-12, RN1219, FGLL, AVE 8112, EVT 101, NP 031112, MK 0752, MK 0952, LX 6171, PAZ417, AV 965, PF 3084014, SYN 114, GSI 953, SAM 315, SAM 531, D-serine,leteprinim potassium, BR 16A (CAS Number 149175-77-9), RPR 107393 (CASNumber 190841-57-7), NXD 2858, REN 1654, CDD 0102, NC 1900 (CAS Number132925-74-7), ciclosporin, NCX 2216 (i.e., (E)-4-(Nitrooxy)butyl3-[4-[2-(2-fluorobiphenyl-4-yl)propanoyloxy]-3-methoxyphenyl]acrylate),NXD 3109, NXD 1191, ZSET 845 (i.e.,3,3-diphenylimidazo[1,2-a]pyridin-2-(3H)-one), ET 002, NT 13, RO 638695(i.e., [1,6-(1,6-dioxohexyl)]dipyrrolidine-(2R)-carboxylic acid),bisnorcymserine, BA 1016, XD 4241, EUK 207 (i.e.,(SP-5-13)-(acetato-κO)[13,16,19,22-tetraoxa-3,6-diazatricyclo[21.3.18,12]octacosa-1(27),2,6,8,10,12(28),23,25-octaene-27,28-diolato(2-)-κN3,κN6, κO27, κO28]manganese), LG 617 inhibitors, ZSET 1446, PAN 811, F14413 (i.e.,2-[5-fluoro-2(S)-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]-4,5-dihydro-1H-imidazole),FP 7832 (i.e., N-[2-(5-methoxy-1-nitroso-1H-indol-3-yl)ethyl]acetamide),ARA 014418 (i.e.,N-(4-methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea), AZD 3102, KP 544(i.e.,2-amino-5-(4-chlorophenylethynyl)-4-(4-trans-hydroxycyclohexylamino)pyrimidine),DP 155,5-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]naphthalene-2-sulfonamide,TAK 070, huperzine, N-[2-(3,5-dimethyladamant-1-yl)ethyl]acetamidinehydrochloride,6-[4-[(dimethylamino)methyl]-5-ethyl-2-methoxyphenyl]pyridin-2-amine,4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine,N-[(1S,2R)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(5S,6R)-5-methyl-6-(neopentyloxy)morpholin-3-yl]propan-2-yl]acetamidehydrochloride,N-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(2R,4R)-4-phenoxypyrrolidin-2-yl]propan-2-yl]-3-[(R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-5-methylbenzamide,R 1589, midafotel, phenserine, coluracetam, physostigmine, cipralisant,nitroflurbiprofen, PPI 1019 (i.e.,(3α,5β,7α,12α)-trihydroxycholan-24-oyl-L-leucyl-L-valyl-L-phenylalanyl-L-phenylalanyl-L-alanine),dapsone, MDL 100453 (CAS Number 129938-34-7), NS 377, midaxifylline,propofol phosphate, metrifonate, ceronapril, tenilsetam, sufoxazine,seglitide, ebiratide, nebracetam, milacemide, iododoxorubicin, SM 10888(CAS Number 129297-21-8), U 80816 (CAS Number 138554-11-7), YM 954 (CASNumber 132041-85-1), SUT 8701 (CAS Number 123577-73-1), apovincamine, FR121196 (CAS Number 133920-65-7), LY 274614 (CAS Number 136109-04-1), CL275838 (CAS Number 115931-65-2), igmesine, K 7259 (CAS Number133667-88-6), vinconate, itasetron, CL 287663 (CAS Number 125109-98-0),WAY 100289 (CAS Number 136013-69-9), SR 46559A (CAS Number 137733-33-6),GYKI 46903 (CAS Number 142999-59-5), L 670548 (CAS Number 121564-89-4),Y 29794 (CAS Number 129184-48-1), AF 125 (CAS Number 7631-86-9), KFM 19(CAS Number 133058-72-7), ST 796 (i.e.,(S)-3-[3-(trifluoromethyl)benzoyl)amino]hexahydroazepin-2-one), RU 33965(CAS Number 122321-05-5), SDZ 210086 (i.e.,(−)-1′,2(S)-Dimethylspiro[1,3-dioxolan-4,4′-piperidine]), L 689660 (CASNumber 144860-79-7), L 689560 (CAS Number 139051-78-8), ST 618 (i.e.,1-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-naphthyl)-4-hydroxypyrrolidin-2-one), U 74500A (CAS Number 110101-65-0), GEA 857 (CASNumber 120493-42-7), BIBN 99 (CAS Number 145301-48-0), DX 9366, ONO 1603(CAS Number 114668-76-7), MDL 102234 (CAS Number 137766-81-5), P 9939(CAS Number 157971-37-4), PD 140532 (CAS Number 157971-39-6),azetirelin, MR 16728 (CAS Number 147614-21-9), dabelotine, MDL 102503(i.e., 8-[1(R)-methyl-2-phenylethyl]-1,3-dipropyl-7H-xanthine), PD141606 (i.e.,(±)-(Z)-3-(3-Phenyl-2-propynyloxyimino)-1-azabicyclo[2.2.1]heptane), SNK882 (CAS Number 152221-12-0), L 696986 (CAS Number 141553-45-9),tazomeline, LY 235959 (CAS Number 137433-06-8),2-(2-thiooxopyrrolidin-1-yl)acetamide, AK 30 NGF, ABT 418 (CAS Number147402-53-7), itameline, HUP 13, sibopirdine, KST 5452 (CAS Number157998-88-4), TJ 54, U 92798 (i.e.,7-[4-[Bis(4-fluorophenyl)methyl]perhydro-1,4-diazepin-1-ylmethyl]-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one),U 92032 (CAS Number 142223-92-5),3-(sulfamoyloxy)estra-1,3,5(10)-trien-17-one, P 11012 (CAS Number164723-36-8), A 82695 (CAS Number 147388-86-1), FR 76659 (CAS Number116904-25-7), apaxifylline, CX 417, 7 MEOTA (CAS Number 5778-80-3), BU4514N (CAS Number 151013-39-7), pregnenolone, mexidol, ST 857 (CASNumber 154755-63-2), RU 49041 (CAS Number 123828-80-8), RU 35929 (CASNumber 111711-47-8), P 878184, P 128 (CAS Number 157716-52-4),eurystatin A, eurystatin B, LK 12, NBI 108, NBI 107, NBI 117, L 705106,bacoside A+B, clausenamide, SM 21 (CAS Number 155156-22-2), alaptide, RS17017 (i.e.,1-(4-Amino-5-chloro-2-methoxyphenyl)-5-(1-piperidinyl)-1-pentanonehydrochloride), AF 150(S) (i.e.,(S)-[1-Methyl-piperidine-4-spiro-(2-methylthiazoline)]), RO 153505 (CASNumber 78771-13-8), PV 113 (i.e.,1,2,3,4-Tetrahydropyrrolo-[1,2-a]-pyrazine), arisugacin, A 98284 (i.e.,2(R)-(3-Methylisoxazol-5-yl) quinuclidine), AP 5 (CAS Number136941-85-0), BD 1054, SDZ NDD 094 (i.e.,bis-(2-(2-methylimidazol-1-yl]methyl)-pyridine-tris(hydrogen-fumarate),AZ 36041 (CAS Number 173324-76-0), quilostigmine, A 84543 (i.e.,3-[1-Methylpyrrolidin-2-(S)-ylmethoxy]pyridine fumarate), BTG 4247(i.e.,(2-[2-Chloroethoxy[4-(dimethylamino)phenyl]phosphoryl]-acetohydrazide),CGP 50068 (CAS Number 158647-49-5), cerebrocrast, desferrinordanoxamine,isolichenan, MHP 133 (i.e.,3-(N,N-dimethylcarbamoyloxy)-1-methyl-2-(4-phenyl-semicarbazonomethyl)pyridiniumchloride), FR 152558 (CAS Number 151098-08-7), GVS 111 (CAS Number157115-85-0), P 11149 (CAS Number 164724-79-2), PDC 008004, KST 2818(CAS Number 158623-26-8), KST 5410 (CAS Number 158623-27-9), RU 52583(CAS Number 123829-33-4), PD 151832 (CAS Number 149929-39-5), UCL 1199(i.e., 4-[2-[(5-Nitropyridin-2-ylsulfanyl)ethyl]-1H-imidazole),isovanihuperzine A, SIB 1765F (CAS Number 179120-52-6), JWS USC 751X(i.e.,3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine),GR 175737 (i.e.,3-(4-Chlorobenzyl)-5-[2-(1H-imidazol-4-yl)ethyl]-1,2,4-oxadiazole), KS505A (CAS Number 131774-53-3), ZTTA 1 (i.e.,N-benzyloxycarbonyl-thioprolyl-thioprolynal-dimethylaceta 1), AGN 190837(CAS Number 136527-40-7), P 10358 (188240-59-7), WAY 131256 (CAS Number174001-71-9), DBO 83 (i.e.,3-(6-chloropyridazin-3-yl)-diazabicyclo[3.2.1]octane dihydrochloridemonohydrate), FUB 181 (CAS Number 152029-80-6), RJR 2557, WSU 2088,LVV-haemorphin-7, M 40 (i.e., galanin[1-12]-Pro3-(Ala-Leu)₂-Ala-NH₂),SIB 1757, SKF 74652 (i.e., [5-chloro-2-(4-methoxyphenyl)-3-benzofuranyl][4-[3-(diethylamino)-propoxy]phenyl]methanone),CGP 71982, SCH 57790 (i.e.,4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]phenyl]-1-piperazineacetonitrile),Putrescine-D-YiAbeta11, DU 14 (i.e., p-O-(sulfamoyl)-N-tetradecanoyltyramine), CLZ 4, SL 340026, PPRT 424, ciproxifan, UR 1827 (i.e.,2-(1-benzylpiperidin-4-yl)-1-[4-(5-methylpyrimidin-4-ylamino)phenyl]-1-ethanone),caproctamine, TGS 20 (i.e., L-pyroglutamil-D-alanine amide), PG 9 (i.e.,alpha-tropanyl 2-[(4-bromo)phenyl]propionate), TEI 3356 (i.e.,(16S)-15-Deoxy-16-hydroxy-16-methyl-9-(O)-methano-DELTA6(9alpha)-prostaglandinI1), LY 392098 (i.e., Thiophene,3-[(2-methylethyl-2)sulphonylaminopropyl-2]phenyl-4-yl-), PG 1000, DM232, NEPP 11 (i.e.,12-iso-15-Deoxy-18-(4-methyl)phenyl-13,14-dihydro-delta7-prostaglandinA1methyl ester), VA 100 (i.e.,(2,3-Dihydro-2-[[(4-fluorobenzoyl)amino]ethyl]-1-methyl-5-phenyl-1H-1,4-benzodiazepine),VA 101 (i.e.,(2,3-dihydro-2-[[(2-thienylcarbonyl)amino]ethyl]-1-methyl-5-phenyl-1H-1,4-benzodiazepine),NC 111585 (i.e.,(3S)-1,3-Bis-[3-[(3-azabicylo[2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1-yl]benzene,2L-(+)-tartate), IN 201, imoproxifan, kanokodiol, picroside I, picrosideII, DM 235 (i.e., 1-(4-Benzoylpiperazin-1-yl)propan-1-one), monoclonalantibody 10D5, JLK2, JLK 6, JLK 7, DAPT (i.e.,N—[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester),huperine X, SGS 111 (i.e., (S)-ethyl2-[1-(2-phenylacetyl)pyrrolidine-2-carboxamido]acetate), NP 7557, C9136, C 7617, R 1485, rofecoxib, velnacrine, montirelin, lazabemide, ORG2766 (CAS Number 50913-82-1), sabeluzole, adafenoxate, CAS Number9061-61-4, ipidacrine, bemesetron, idazoxan, linopirdine, selfotel,suritozole, milameline, xanomeline, TJ 960, fasoracetam, eptastigmine,ensaculin, zanapezil, posatirelin, zacopride, RS 86 (CAS Number3576-73-6), ORG 5667 (CAS Number 37552-33-3), RX 77368 (CAS Number76820-40-1), BMS 181168 (CAS Number 123259-91-6), BY 1949 (CAS Number90158-59-1), AWD 5239 (CAS Number 109002-93-9), YM 796 (171252-79-2),aloracetam, CI 933 (CAS Number 91829-95-7), ST 793 (CAS Number99306-37-3), cebaracetam, zifrosilone, talsaclidine, alvameline, JTP2942 (148152-77-6), OPC 14117 (CAS Number 103233-65-4), elziverine, AP521 (i.e.,N-(1,3-Benzodioxol-5-ylmethyl)-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3(R)-carboxamidehydrochloride), S 8510 (CAS Number 151466-23-8), JTP 4819 (CAS Number162203-65-8), icopezil, SC 110, FK 960 (CAS Number 133920-70-4), DMP 543(CAS Number 160588-45-4), ganstigmine, CI 1017 (i.e.,(R)-(−)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one,O-(3-(3′-methoxyphenyl)-2-propynyl)-oxime maleate), T 82 (i.e.,2-[2-(1-Benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-onehemifumarate), NGD 971, vaccine ofAspartyl-alanyl-glutamyl-phenylalanyl-arginyl-histidyl-aspartyl-seryl-glycyl-tyrosyl-glutamyl-valyl-histidyl-histidyl-glutaminyl-lysyl-leucyl-valyl-phenylalanyl-phenylalanyl-alanyl-glutamyl-aspartyl-valyl-glycyl-seryl-asparaginyl-lysyl-glycyl-alanyl-isoleucyl-isoleucyl-glycyl-leucyl-methionyl-valyl-glycyl-glycyl-valyl-valyl-isoleucyl-alanine,PBT 1 (CAS Number 130-26-7), TCH 346, FK 962 (i.e.,N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide), voxergolide, KW 6055 (CASNumber 63233-46-5), thiopilocarpine, ZK 93426 (CAS Number 89592-45-0),SDZ NVI 085 (CAS Number 104195-17-7), CI 1002 (CAS Number 149028-28-4),Z 321 (CAS Number 130849-58-0), mirisetron, CHF 2060 (i.e.,N-Heptylcarbamic acid2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2-oxazino[6,5-b]indol-6-ylester-L-tartrate), gedocarnil, terbequinil, HOE 065 (CAS Number123060-44-6), SL 650102, GR 253035, ALE 26015, SB 271046 (i.e.,5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide),iAbeta5, SCH 211803 (i.e., Piperidine,1-[1-(3-methyl-2-aminophenyl)carbonylpiperidin-4yl]-4-[(3-chlorophenyl)sulphonylphenyl-4]methyl-),EVT 301, alpha-Linolenic acid/linoleic acid, Kamikihi-To, siagoside, FG7142 (CAS Number 78538-74-6), RU 47067 (CAS Number 111711-92-3), RU35963 (CAS Number 139886-03-6), FG 7080 (CAS Number 100332-18-1), E 2030(CAS Number 142007-70-3), transforming growth factor beta-1, A 72055(i.e., 2′,1-Dimethylspiro[piperidine-4,5′oxazolidine]-3-carboxaldehyde),NS 626, dimiracetam, GT 3001, GT 2501, GT 2342, GT 2016 (CAS Number152241-24-2), ORG 20091 (CAS Number 141545-50-8), BCE 001 (CAS Number95678-81-2), CGP 35348 (CAS Number 123690-79-9), WAY 100635 (CAS Number146714-97-8), E 4804 (CAS Number 162559-34-4), LIGA 20 (CAS Number126586-85-4), NG 121 (i.e.,2-[4,8-Dimethyl-3(E),7(E)-nonadienyl]-3,5-dihydroxy-2-methyl-3,4,7,9-tetrahydro-2H-furo[3,4-h]-1-benzopyran-7-one),MF 247 (i.e., N-[10-(Diethylamino)decyl]carbamic acid(3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylester), JTP 3399 (i.e.,N-Benzyl-2(S)-[2(S)-(phenoxyacetyl)pyrrolidin-1-ylcarbonyl]pyrrolidine-1-carboxamide),KF 17329, thioperamide, F 3796 (i.e.,1-[2-(1-Benzylpiperidin-4-yl)ethyl]-3-[3,4-(methylene-dioxy)benzoyl]thiourea),GT 4001, GT 4002, FPL 14995 (CAS Number 123319-03-9), RU 34332 (CASNumber 137157-58-5), SR 96777A (CAS Number 115767-94-7), SIB T1980, NS649 (CAS Number 146828-02-6), PD 142505 (CAS Number 149929-08-8), GYKI52466 (CAS Number 102771-26-6), RO 246173 (CAS Number 159723-57-6), SCH50911 (CAS Number 160415-07-6), Z 4105 (CAS Number 119737-52-9), RS67333 (CAS Number 168986-60-5), NS 1546, ZM 241385 (CAS Number139180-30-6), RO 249975 (i.e.,[1S,3S(2′S),5R]-3-(1-Benzyl-5-oxopyrrolidin-2-ylmethyl)-5-(1H-imidazol-5-ylmethyl)cyclohexane-1-acetamide),AF 185 (i.e.,8-Methyl-3-(2-propynyl)-1,3,8-triazaspiro[4,5]decane-2,4-dione), CEP427, CX 423, CX 438, CX 480, CDP-ethanolamine, GT 4003, GT 4011, GT5011, MS 430 (CAS Number 122113-44-4), MBF 379 (i.e.,[3,3-Bis(hydroxymethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-5-yl][3,5-dihydroxy-4-(2-oxo-2-phenylethoxy)phenyl]methanone),NGD 187 (CAS Number 163565-48-8), DUP 856, MR 3066, MF 8615 (i.e.,5-Amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyrano-[3,4-b]quinoline),himbacine, ABS 300, RJR 2403 (CAS Number 538-79-4), MF 268 (CAS Number174721-00-7), RO 465934 (i.e., N,N-Dimethylcarbamic acid3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benz[e]indol-6-ylester), NS 393, RGH 2716 (CAS Number 134069-68-4), WIN 678702(12,12-Bis(3-furyl)-6,11-dihydro-6,11-ethanobenzo[b]quinoliziniumchloride), RS 66252 (i.e.,1-Butyl-2-[(2-(2H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1H-indole-3-carboxylicacid), AIT 034 (CAS Number 138117-48-3), NG 012 (CAS Number131774-53-3), PD 142012 (CAS Number 5778-84-7), GT 4054, GT 4077, GT4035, P 26 (CAS Number 152191-74-7), RGH 5279 (i.e.,(−)-(13aR,13bS)-13a-Ethyl-2,3,5,6,13a,13b-hexahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine-12-carboxylicacid 2-acetoxyethyl ester), AIT 083, CeNeS, estradiol (i.e.,1,3,5(10)-Estratriene-3,17beta-diol), WAY 132983((3R,4R)-3-(3-hexylsulfanylpyrazin-2-yloxy)-1-azabicyclo[2.2.1]heptanehydrochloride), ABS 205, ABS 401, SX 3507 (i.e.,3-(3-Propyl-1,2,4-oxadiazol-5-yl)quinoxaline-2(1H)-one), ARR 17779(i.e., (−)-Spiro[1-azabicyclo[2.2.2]octane-3,5-oxazolidine]-2-one), XE991 (i.e., 10,10-bis(4-Pyridylmethyl)anthracen-10(9H)-one),phenethylnorcymserine, RO 657199, RJR 1781 (i.e.,R(+)-2-(3-pyridyl)-1-azabicyclo[2.2.2.]octane), RJR 1782 (i.e.,S(−)-2-(3-pyridyl)-1-azabicyclo[2.2.2.]octane), gilatide, tolserine, TC2559 (i.e., (E)-N-Methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine), ER127528 (i.e.,1-(3-Fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanone-2-yl)methyl]piperidinehydrochloride), thiatolserine, targacept, axonyx, cymserine,thiacymserine, monoclonal antibody 266, Apan-CH, DP 103, SPI 339 (i.e.,4-[3-(4-Oxo-4,5,6,7-tetrahydroindol-1-yl)propionylamino]benzoic acidethyl ester), S 37245 (i.e.,4-(1,4-Benzodioxan-5-yl)-1-[3(S)-hydroxy-5-nitro-indan-2-yl]-piperazine),LLG 88, AZD 2858, trometamol, AN 240, NG 002 (i.e.,5-Hydroxy-5-(2-hydroxy-1-methylethyl)-4-methoxyfuran-2(5H)-one), UCB29427 (i.e.,2-Cyclopropyl-4-(cyclopropylamino)-6-(morpholino)-1,3,5-triazine),TRH-SR, RO 401641 (CAS Number 122199-02-4), MPV 1743AIII (CAS Number150586-64-4), IDRA 21 (CAS Number 22503-72-6), CEP 431, ACPD (CAS Number67684-64-4), CT 3577 (i.e.,3,7-Dimethyl-1-[11-(3,4,5-trimethoxybenzylamino)-11-oxoundecyl]xanthine),CT 2583, NXD 9062, Desferrinordanoxamine, DP b99, PBT 1, T 817MA,Alfatradiol (CAS No. 57-91-0), AL 108, SL 650102, RS 67333 (CAS No.168986-60-5), RS 17017, SGS 518, SYN 114, SB 271046, RO 657199, PRX07034, Suritozole (CAS No. 110623-33-19), Terbequinil (CAS No.113079-82-6), FG 7142 (CAS No. 78538-74-6). RU 34332 (CAS No.137157-58-5), SX 3507, RO 153505 (CAS No. 78771-13-8), RU 33965 (CAS No.122321-05-5), S 8510 (CAS No. 151466-23-8), Sabeluzole (CAS No.104383-17-7), Cerebrocrast (CAS No. 118790-71-9), NS 626, NS 649 (CASNo. 146828-02-6), U 92032 (CAS No. 142223-92-5), MEM 1003, U 92798, RGH2716 (CAS No. 134069-68-4), Safinamide (CAS No. 133865-89-1), AZD 0328,MEM 63908, ABT 418 (CAS No. 147402-53-7), ARR 17779, RJR 2403 (CAS No.538-79-4), TC 2559, A 82695 (CAS No. 147388-86-1), A 84543, A 98284, DBO83, RJR 2557, SIB 1765F (CAS No. 179120-52-6), GTS 21 (CAS No.156223-05-1), MEM 3454, SIB 1553A, EVP 6124, SSR 180711, ABT 089 (CASNo. 161417-03-4), ABT 107, ABT 560, TC 5619, TAK 070,N-[(1S,2R)-3-(3,5-Difluorophenyl)-1-hydroxy-1-[(5S,6R)-5-methyl-6-(neopentyloxy)morpholin-3-yl]propan-2-yl]acetamidehydroCl, 6-Fluoro-5-(2-fluoro-5-methylphenyl)-3,4-dihydropyridine,2-Amino-6-[2-(3-methoxybiphenyl-3-yl)ethyl]-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one,AZD 1080, ARA 014418, XD 4241, Z 321 (CAS No. 130849-58-0), ONO 1603(CAS No. 114668-76-7), JTP 3399, Eurystatin A (CAS No. 137563-63-4),Eurystatin B (CAS No. 137563-64-5), P 128 (CAS No. 157716-52-4), Y 29794(CAS No. 129184-48-1), ZTTA 1, JTP 4819 (CAS No. 162203-65-8),Monoclonal antibody 266, duloxetine, escitalopram oxalate, fluoxetine,fluvoxamine maleate, paroxetine, sertraline, dapoxetine, desvenlafaxine,sibutramine, nefazodone, milnacipran, desipramine, duloxetine, andbicifadine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in detail with reference toexamples; however, the examples are provided only for illustrationpurposes. The prophylactic or therapeutic agent for a disease caused byAβ according to the present invention is not limited to the followingspecific examples in any cases. A person skilled in the art can fullyimplement the present invention by making various modifications to notonly the following reference examples and examples but also the claimsof the present specification, and such modifications are within thescope of the claims of the present specification.

When the compound in the Examples include stereoisomers, and theabsolute configuration has not been determined, there are the cases thatthe name of the compounds with optical rotating power and its chemicalstructural formula are not described correspondingly in the followingExamples.

The following abbreviations are used in the following examples.

DMF: N,N-Dimethylformamide

THF: Tetrahydrofuran

EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

HOBT: 1-Hydroxybenzotriazole

IPEA: Diisopropylethylamine

IPA: 2-Propanol

DMAP: 4-(Dimethylamino)pyridine

TEA: Triethylamine

CDI: Carbonyldiimidazole

TBAF: Tetrabutylammonium fluoride

DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

t: Tertiary

BOPCl: Bis(2-oxo-3-oxazolidinyl)phosphonic chloride

DIBAL-H: Diisobutylaluminum hydride

DAST: Diethylaminosulfur trifluoride

BINAP: 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl

Chromatography was performed using BW-300 manufactured by Fuji SilysiaChemical Ltd. as a carrier unless otherwise specified.

LC-MS: High performance liquid chromatography for preparative isolationof a target compound using mass spectroscopy. As an elution solvent, a10% to 99% linear gradient system of water containing 0.1%trifluoroacetic acid and acetonitrile containing 0.1% trifluoroaceticacid was used.

Reference Examples 1 and 2 Synthesis of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acidN′-{(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acryloyl}hydrazide

IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution of5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride(83 mg) and(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(CAS No. 870837-77-7, 68 mg) in methylene chloride (5 mL), and thereaction solution was stirred at room temperature for 18 hours. Ethylacetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 112 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 522 [M⁺+H].

Synthesis of5-{(E)-2-{5-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-[1,3,4]oxadiazol-2-yl}vinyl}-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine

A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acidN′-{(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acryloyl}hydrazide(112 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for 3.5hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure to obtain 108 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 504 [M⁺+H].

Synthesis of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of5-{(E)-2-{5-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-[1,3,4]oxadiazol-2-yl}vinyl}-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine(495 mg) in acetic acid (2 mL) was stirred at 150° C. for 25 hours. Thereaction solution was left to cool to room temperature. Then, ethylacetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (carrier: Chromatorex NH; elution solvent:heptane:ethyl acetate=1:1→ethyl acetate) to obtain a racemate of thetitle compound. The resulting racemate was separated by CHIRALPAK™ IAmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain the title optically active compound with aretention time of 20 minutes and positive optical rotation (11 mg, >99%ee) and the title optically active compound with a retention time of 25minutes and negative optical rotation (12 mg, >99% ee).

The property values of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.97-2.06 (m, 1H), 2.07-2.25 (m, 2H), 2.29 (s,3H), 2.34-2.42 (m, 1H), 3.97 (s, 3H), 4.23-4.30 (m, 3H), 6.81 (dd,J=8.0, 6.4 Hz, 2H), 7.08 (d, J=16.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H),7.49 (d, J=16.0 Hz, 1H), 7.52 (brs, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34(brs, 1H).

The property values of(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.97-2.06 (m, 1H), 2.07-2.25 (m, 2H), 2.29 (s,3H), 2.34-2.42 (m, 1H), 3.97 (s, 3H), 4.23-4.30 (m, 3H), 6.81 (dd,J=8.0, 6.4 Hz, 2H), 7.08 (d, J=16.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H),7.49 (d, J=16.0 Hz, 1H), 7.52 (brs, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34(brs, 1H).

Reference Examples 3 and 4 Synthesis of(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

Sodium hydride (containing 40% of mineral oil, 4 mg) was added to asolution of2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridinesynthesized by the method in Reference Examples 1 and 2 (21 mg) in DMF(2 mL), and the reaction solution was stirred at room temperature for 30minutes while bubbling with oxygen gas. Ethyl acetate and saturatedaqueous ammonium chloride were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting racemic crude product of the title compound wasseparated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the titleoptically active compound with a retention time of 7 minutes andnegative optical rotation (3.7 mg, >99% ee) and the title opticallyactive compound with a retention time of 10 minutes and positive opticalrotation (3.2 mg, >99% ee).

The property values of(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

ESI-MS; m/z 483 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.16 (m, 2H), 2.28(s, 3H), 2.30-2.39 (m, 1H), 2.40-2.53 (m, 1H), 3.91 (s, 3H), 4.19-4.28(m, 1H), 4.29-4.36 (m, 1H), 7.00-7.05 (m, 3H), 7.33 (d, J=1.6 Hz, 1H),7.41 (d, J=16.8 Hz, 1H), 7.46 (brs, 1H), 8.02 (d, J=1.6 Hz, 1H), 8.28(brs, 1H).

The property values of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

ESI-MS; m/z 483 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.16 (m, 2H), 2.28(s, 3H), 2.30-2.39 (m, 1H), 2.40-2.53 (m, 1H), 3.91 (s, 3H), 4.19-4.28(m, 1H), 4.29-4.36 (m, 1H), 7.00-7.05 (m, 3H), 7.33 (d, J=1.6 Hz, 1H),7.41 (d, J=16.8 Hz, 1H), 7.46 (brs, 1H), 8.02 (d, J=1.6 Hz, 1H), 8.28(brs, 1H).

Examples 1 and 2 Synthesis of(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylonitrile

A lithium hydroxide monohydrate powder (2.23 g) was added to asuspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (CASNo. 870837-18-6, 10 g) and diethyl cyanomethylphosphonate (8.2 g) in THF(50 ml) under ice-cooling, and the reaction solution was stirred at thesame temperature for one hour. Ethyl acetate (200 mL) and water wereadded to the reaction solution, and the organic layer was separated. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then filtered through a silica gel pad (carrier:Chromatorex™ NH). The filtrate was concentrated under reduced pressure.The resulting residue was crystallized from ethyl acetate and hexane,and the crystals were collected by filtration. The resulting crystalswere dried under reduced pressure to obtain 7.49 g of the titlecompound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 3.91 (s, 3H), 5.90 (d, J=16.8 Hz,1H), 6.93 (d, J=0.8 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.13 (dd, J=8.0,1.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.39 (d, J=16.8 Hz, 1H), 7.74 (d,J=0.8 Hz, 1H).

Synthesis of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride

A suspension of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylonitrile (7.45g) in ethanol (75 mL) was bubbled with hydrogen chloride gas underice-cooling for 10 minutes and at room temperature for 15 minutes, andthen the reaction solution was stirred at room temperature overnight.The reaction solution was concentrated under reduced pressure. Then,ethanol and diethyl ether were added to the residue, and theprecipitated powder was collected by filtration. The resulting powderwas crystallized from ethanol and diethyl ether to obtain 9.22 g of thetitle compound. The property values of the compound are as follows.

ESI-MS; m/z 286 [M⁺+H-2HCl]. ¹H-NMR (DMSO-D₆) δ (ppm): 1.46 (t, J=6.8Hz, 3H), 2.35 (s, 3H), 3.93 (s, 3H), 4.54 (q, J=6.8 Hz, 2H), 7.18 (d,J=16.0 Hz, 1H), 7.50 (dd, J=8.0, 1.2 Hz, 1H), 7.68-7.77 (m, 3H), 8.01(d, J=16.0 Hz, 1H), 9.35 (s, 1H).

Synthesis of 5-chloro-2-(3-fluorophenyl)pentanoic acid

A solution of 3-fluorophenylacetic acid (500 mg) in THF (15 mL) wasstirred at −78° C. for 5 minutes. A 2.66 M solution of n-butyl lithiumin hexane (2.44 mL) was added, and the reaction solution was stirred at−78° C. for three hours. Thereafter, the reaction solution was stirredat 0° C. for one hour, 1-bromo-3-chloropropane was added, and thereaction solution was stirred at room temperature for 17 hours.Thereafter, ethyl acetate and 1 N aqueous hydrochloric acid were addedto the reaction solution, and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 734 mg of the titlecompound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.64-1.85 (m, 2H), 1.90-2.02 (m, 1H), 2.14-2.32(m, 1H), 3.46-3.61 (m, 3H), 6.93-7.11 (m, 3H), 7.23-7.37 (m, 1H).

Synthesis of tert-butylN′-[5-chloro-2-(3-fluorophenyl)pentanoyl]hydrazinecarboxylate

IPEA (1.9 mL), HOBt (859 mg) and EDC (1.22 g) were added to a solutionof 5-chloro-2-(3-fluorophenyl)pentanoic acid (734 mg) and tert-butylcarbazate (504 mg) in DMF (10 mL), and the reaction solution was stirredat room temperature for seven hours. Ethyl acetate and water were addedto the reaction solution, and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 711 mg of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.43 (s, 9H), 1.56-2.06 (m, 3H), 2.12-2.32 (m,1H), 3.36-3.58 (m, 3H), 6.55 (brs, 1H), 6.90-7.16 (m, 3H), 7.20-7.34 (m,1H), 7.67 (brs, 1H).

Synthesis of(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of 4 N hydrochloric acid in ethyl acetate (12.1 mL) was addedto tert-butylN′-[5-chloro-2-(3-fluorophenyl)pentanoyl]hydrazinecarboxylate (711 mg),and the reaction solution was stirred at room temperature for two hours.The reaction solution was concentrated under reduced pressure to obtaina crude product of 5-chloro-2-(3-fluorophenyl)pentanoic acid hydrazidehydrochloride. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (576 mg) and triethylamine (1.24 mL) in ethanol (10 mL)was added to a solution of the resulting crude product of5-chloro-2-(3-fluorophenyl)pentanoic acid hydrazide hydrochloride andtriethylamine (1 mL) in ethanol (10 mL), and the reaction solution wasstirred at 80° C. in a nitrogen atmosphere for 23 hours. The reactionsolution was cooled to room temperature and then the solvent wasevaporated under reduced pressure. Ethyl acetate and saturated sodiumbicarbonate water were added to the resulting residue, and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (carrier:Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethylacetate→ethyl acetate:methanol=9:1) and further purified by silica gelcolumn chromatography (elution solvent: ethyl acetate→ethylacetate:methanol=9:1) to obtain 306 mg of a racemate of the titlecompound. The resulting racemate (152 mg) was separated by CHIRALPAK™ IAmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain a (+)-isomer of the title opticallyactive compound with a retention time of 14 minutes (60 mg; >99% ee) anda (−)-isomer of the title optically active compound with a retentiontime of 15.5 minutes (61 mg; 92% ee).

The property values of(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 430 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.46 (m, 7H), 3.85(s, 3H), 4.21-4.38 (m, 3H), 6.81-7.02 (m, 4H), 7.06 (d, J=16.0 Hz, 1H),7.10-7.24 (m, 3H), 7.26-7.34 (m, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.69(brs, 1H).

The property values of(−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 430 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.46 (m, 7H), 3.85(s, 3H), 4.21-4.38 (m, 3H), 6.81-7.02 (m, 4H), 7.06 (d, J=16.0 Hz, 1H),7.10-7.24 (m, 3H), 7.26-7.34 (m, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.69(brs, 1H).

Examples 3 and 4 Synthesis of(−)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-oneand(+)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one

119 mg of a racemate of the title compound was obtained from4-cyanophenylacetic acid (1 g) by the same method as in Examples 1 and2. The racemate (60 mg) was separated by CHIRALPAK™ IB manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) toobtain a (−)-isomer of the title optically active compound with aretention time of 18.5 minutes (22.3 mg; 98% ee) and a (+)-isomer of thetitle optically active compound with a retention time of 33 minutes (23mg; 98% ee).

The property values of(−)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-oneare as follows.

ESI-MS; m/z 496 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 0.95 (t, J=7.2 Hz, 3H),1.34-1.46 (m, 2H), 1.66-1.76 (m, 2H), 2.00-2.48 (m, 7H), 2.94 (t, J=7.6Hz, 2H), 3.85 (s, 3H), 4.24-4.35 (m, 2H), 4.36-4.43 (m, 1H), 6.91 (brs,1H), 7.06 (d, J=16.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.18-7.30 (m, 3H), 7.50(d, J=16.4 Hz, 1H), 7.73 (brs, 1H), 7.87-7.97 (m, 2H).

The property values of(+)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-oneare as follows.

ESI-MS; m/z 496 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 0.95 (t, J=7.2 Hz, 3H),1.34-1.46 (m, 2H), 1.66-1.76 (m, 2H), 2.00-2.48 (m, 7H), 2.94 (t, J=7.6Hz, 2H), 3.85 (s, 3H), 4.24-4.35 (m, 2H), 4.36-4.43 (m, 1H), 6.91 (brs,1H), 7.06 (d, J=16.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.18-7.30 (m, 3H), 7.50(d, J=16.4 Hz, 1H), 7.73 (brs, 1H), 7.87-7.97 (m, 2H).

Examples 5 and 6 Synthesis of(−)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

242.4 mg of a racemate of the title compound was obtained from4-isopropylphenylacetic acid (1 g) by the same method as in Examples 1and 2. The racemate (100 mg) was separated by CHIRALCEL™ OJ-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain a (−)-isomer of the title optically activecompound with a retention time of 8.5 minutes (40.7 mg; >99% ee) and a(+)-isomer of the title optically active compound with a retention timeof 15 minutes (39.1 mg; 96% ee).

The property values of(−)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 454 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.23 (d, J=6.8 Hz, 6H),1.80-2.40 (m, 7H), 2.82-2.95 (m, 1H), 3.85 (s, 3H), 4.20-4.35 (m, 3H),6.90 (brs, 1H), 6.98-7.24 (m, 8H), 7.51 (d, J=16.4 Hz, 1H), 7.67-7.72(m, 1H).

The property values of(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 454 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.23 (d, J=6.8 Hz, 6H),1.80-2.40 (m, 7H), 2.82-2.95 (m, 1H), 3.85 (s, 3H), 4.20-4.35 (m, 3H),6.90 (brs, 1H), 6.98-7.24 (m, 8H), 7.51 (d, J=16.4 Hz, 1H), 7.67-7.72(m, 1H).

Examples 7 and 8 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

235.6 mg of a racemate of the title compound was obtained from(4-methylsulfanylphenyl)acetic acid (500 mg) by the same method as inExamples 1 and 2. The racemate (100 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain a (−)-isomer of the title opticallyactive compound with a retention time of 21 minutes (49.2 mg; >99% ee)and a (+)-isomer of the title optically active compound with a retentiontime of 29.5 minutes (49.6 mg; >99% ee).

The property values of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 458 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.98-2.40 (m, 7H), 2.47(s, 3H), 3.85 (s, 3H), 4.21-4.34 (m, 3H), 6.87-6.93 (m, 1H), 7.01-7.28(m, 8H), 7.50 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 458 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.98-2.40 (m, 7H), 2.47(s, 3H), 3.85 (s, 3H), 4.21-4.34 (m, 3H), 6.87-6.93 (m, 1H), 7.01-7.28(m, 8H), 7.50 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Example 9 Synthesis of8-(4-methanesulfonylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

mCPBA (6.83 mg) was added to a solution of(−)-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineobtained in Example 7 (4.5 mg) in chloroform (1 mL), and the reactionsolution was stirred at room temperature for one hour. Brine and ethylacetate were added to the reaction solution and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(carrier: Chromatorex NH; elution solvent: ethyl acetate→ethylacetate:methanol=9:1) to obtain 0.44 mg of the title compound.

The property values of8-(4-methanesulfonylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 490 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.96-2.48 (m, 7H), 3.05(s, 3H), 3.85 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.42 (t, J=7.2 Hz, 1H),6.91 (brs, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.10-7.30 (m, 3H), 7.38 (d,J=8.4 Hz, 2H), 7.49 (d, J=16.4 Hz, 1H) 7.69 (d, J=0.8 Hz, 1H), 7.92 (d,J=8.4 Hz, 2H).

Examples 10 and 11 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

258.6 mg of a racemate of the title compound was obtained fromthiophen-2-ylacetic acid (500 mg) by the same method as in Examples 1and 2. The racemate (106 mg) was separated by CHIRALCEL™ OJ-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain a (−)-isomer of the title optically activecompound with a retention time of 11 minutes (51.5 mg; >99% ee) and a(+)-isomer of the title optically active compound with a retention timeof 19 minutes (52.1 mg; 98% ee).

The property values of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 418 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.03-2.48 (m, 7H), 3.86(s, 3H), 4.16-4.32 (m, 2H), 4.63 (t, J=6.0 Hz, 1H), 6.88-6.98 (m, 3H),7.07 (d, J=16.8 Hz, 1H), 7.12-7.24 (m, 4H), 7.54 (d, J=16.8 Hz, 1H),7.69 (d, J=1.2 Hz, 1H).

The property values of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 418 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.03-2.48 (m, 7H), 3.86(s, 3H), 4.16-4.32 (m, 2H), 4.63 (t, J=6.0 Hz, 1H), 6.88-6.98 (m, 3H),7.07 (d, J=16.8 Hz, 1H), 7.12-7.24 (m, 4H), 7.54 (d, J=16.8 Hz, 1H),7.69 (d, J=1.2 Hz, 1H).

Example 12 Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-[1-phenylmethy-(E)-lidene]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butyl 5-chloro-2-[1-phenylmethy-(E)-lidene]pentanoate

Ethanol (30 mL), benzaldehyde (3 mL) and lithium hydroxide monohydrate(3.71 g) were added to a solution of a solution of tert-butyl5-chloro-2-(diethoxyphosphoryl)pentanoate (CAS No. 870843-25-7) (10.7 g)in THF (90 mL), and the reaction solution was stirred at roomtemperature for 19.5 hours. Thereafter, ethyl acetate and saturatedsodium bicarbonate water were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain6.57 g of the title compound. The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.55 (S, 9H), 1.96-2.14 (m, 2H), 2.59-2.68 (m,2H), 3.56 (t, J=6.8 Hz, 2H), 7.23-7.41 (m, 5H), 7.62 (brs, 1H).

Synthesis of 5-chloro-2-[1-phenylmethy-(E)-lidene]pentanoic acid

Anisole (1.16 mL) was added to tert-butyl5-chloro-2-[1-phenylmethy-(E)-lidene]pentanoate (1 g). Trifluoroaceticacid (5 mL) was further added under ice-cooling, and the reactionsolution was stirred in a nitrogen atmosphere under ice-cooling for fourhours. Thereafter, the reaction solution was concentrated under reducedpressure and the resulting residue was dissolved in ethyl acetate at 80°C. The solution was left to stand at room temperature and theprecipitated crystals were collected by filtration. The crystalscollected by filtration was washed with ethyl acetate:heptane=1:1 toobtain 188.6 mg of the title compound. The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.02-2.22 (m, 2H), 2.67-2.77 (m, 2H), 3.60 (t,J=6.4 Hz, 2H), 7.32-7.47 (m, 5H), 7.86 (brs, 1H).

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-[1-phenylmethy-(E)-lidene]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

IPEA (4 mL), HOBt (1.81 g) and EDC (2.56 g) were added to a solution of5-chloro-2-[1-phenylmethy-(E)-lidene]pentanoic acid (1.5 g) andtert-butyl carbazate (1.06 g) in DMF (20 mL), and the reaction solutionwas stirred at room temperature for 2.5 hours. Ethyl acetate and waterwere added to the reaction solution and the organic layer was separated.The resulting organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (elution solvent: heptane-ethylacetate system) to obtain an (E)/(Z) mixture of tert-butylN′-{5-chloro-2-[1-phenylmethylidene]pentanoyl}hydrazinecarboxylate (1.97g). A solution of 4 N hydrochloric acid in ethyl acetate (12.1 mL) wasadded to the resulting (E)/(Z) mixture of tert-butylN′-{5-chloro-2-[1-phenylmethylidene]pentanoyl}hydrazinecarboxylate(0.726 g), and the reaction solution was stirred at room temperature forseven hours. The reaction solution was concentrated under reducedpressure. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (0.576 g) and triethylamine (1.24 mL) in ethanol (10 mL)was added to a solution of the resulting residue and triethylamine (1mL) in ethanol (10 mL). The reaction solution was stirred at 80° C. in anitrogen atmosphere for 16 hours. The reaction solution was cooled toroom temperature and then the solvent was evaporated under reducedpressure. Ethyl acetate and saturated sodium bicarbonate water wereadded to the resulting residue, and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane:ethyl acetate=1:1→ethyl acetate→ethylacetate:methanol=9:1) and further purified by silica gel columnchromatography (elution solvent: ethyl acetate→ethylacetate:methanol=9:1). Then, the purified product was separated byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: ethanol) to obtain the title compound with a retentiontime of 33 minutes (12.3 mg).

The property values of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-[1-phenylmethy-(E)-lidene]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 424 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.11-2.21 (m, 2H), 2.30(s, 3H), 2.93-3.01 (m, 2H), 3.89 (s, 3H), 4.29 (t, J=6.0 Hz, 2H), 6.92(brs, 1H), 7.10 (d, J=16.0 Hz, 1H), 7.16-7.46 (m, 8H), 7.62 (d, J=16.0Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.79 (brs, 1H).

Examples 13 and 14 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

244.7 mg of a racemate of the title compound was obtained fromthiophen-3-ylacetic acid (500 mg) by the same method as in Examples 1and 2. The racemate (103 mg) was separated by CHIRALCEL™ OJ-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain a (−)-isomer of the title optically activecompound with a retention time of 11 minutes (47.1 mg; >99% ee) and a(+)-isomer of the title optically active compound with a retention timeof 19.5 minutes (45.9 mg).

The property values of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 418 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.00-2.42 (m, 7H), 3.86(s, 3H), 4.16-4.32 (m, 2H), 4.45 (t, J=5.2 Hz, 1H), 6.91 (brs, 1H),6.98-7.24 (m, 6H), 7.31 (dd, J=3.2, 5.2 Hz, 1H), 7.54 (d, J=16.0 Hz,1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thiophen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 418 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.00-2.42 (m, 7H), 3.86(s, 3H), 4.16-4.32 (m, 2H), 4.45 (t, J=5.2 Hz, 1H), 6.91 (brs, 1H),6.98-7.24 (m, 6H), 7.31 (dd, J=3.2, 5.2 Hz, 1H), 7.54 (d, J=16.0 Hz,1H), 7.69 (d, J=1.2 Hz, 1H).

Examples 15 and 16 Synthesis of(+)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butyl (3-benzyl-2-oxopiperidin-1-yl)carbamate

10% palladium-carbon powder (50.36% aqueous, 1.92 g) was added to asolution of the (E)/(Z) mixture of tert-butylN′-[5-chloro-2-(1-phenylmethylidene)pentanoyl]hydrazinecarboxylateobtained in the process of Example 12 in ethanol (20 mL), and thereaction solution was stirred in a hydrogen atmosphere at roomtemperature for 10 days. Thereafter, the reaction solution was filteredthrough celite and the solvent was evaporated under reduced pressure.DBU (0.598 mL) was added to a solution of the resulting residue in THF(50 mL) and the mixture was heated under reflux for 44 hours.Thereafter, the solvent was evaporated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 727 mg of thetitle compound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.36-1.60 (m, 10H), 1.70-1.98 (m, 3H), 2.60-2.78(m, 2H), 3.36-3.48 (m, 1H), 3.50-3.66 (m, 2H), 6.69 (brs, 1H), 7.11-7.32(m, 5H).

Synthesis of(+)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of 4 N hydrochloric acid in ethyl acetate (13 mL) was addedto tert-butyl (3-benzyl-2-oxopiperidin-1-yl)carbamate (727 mg), and thereaction solution was stirred at room temperature for three hours. Thereaction solution was concentrated under reduced pressure. IPEA (2.45mL), HOBT (646 mg) and EDC (916 mg) were added to a solution of theresulting residue and(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (CASNo. 970839-41-1, 617 mg) in DMF (15 mL), and the reaction solution wasstirred at room temperature for 25 hours. Ethyl acetate and water wereadded to the reaction solution and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. A solution of the resultingresidue in phosphorus oxychloride (20 mL) was heated under reflux for1.5 hours. The reaction solution was left to cool to room temperatureand then concentrated under reduced pressure. Acetic acid (12 mL) andammonium acetate (7.34 g) were added to the resulting residue, and thereaction solution was stirred at 150° C. for 2.5 hours. The reactionsolution was left to cool to room temperature and then concentratedunder reduced pressure. Ethyl acetate and saturated sodium bicarbonatewater were added to the resulting residue, and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (carrier:Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethylacetate→ethyl acetate:methanol=9:1) and further purified by silica gelcolumn chromatography (elution solvent: ethyl acetate→ethylacetate:methanol=9:1) to obtain 10.3 mg of a racemate of the titlecompound. The resulting racemate (10.3 mg) was separated by CHIRALCEL™OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm;mobile phase: hexane:ethanol=1:1) to obtain a (+)-isomer of the titleoptically active compound with a retention time of 8 minutes (2.83mg, >99% ee) and a (−)-isomer of the title optically active compoundwith a retention time of 13.5 minutes (3.27 mg, >99% ee).

The property values of(+)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 426 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.50-1.76 (m, 1H),1.86-2.02 (m, 2H), 2.06-2.18 (m, 1H), 2.30 (s, 3H), 2.76 (dd, J=10.4,13.2 Hz, 1H), 3.16-3.28 (m, 1H), 3.65 (dd, J=3.6, 13.2 Hz, 1H), 3.89 (s,3H), 4.03-4.13 (m, 1H), 4.14-4.24 (m, 1H), 6.92 (brs, 1H), 7.09 (d,J=16.4 Hz, 1H), 7.16-7.35 (m, 8H), 7.58 (d, J=16.4 Hz, 1H), 7.71 (d,J=1.2 Hz, 1H).

The property values of(−)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 426 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.50-1.76 (m, 1H),1.86-2.02 (m, 2H), 2.06-2.18 (m, 1H), 2.30 (s, 3H), 2.76 (dd, J=10.4,13.2 Hz, 1H), 3.16-3.28 (m, 1H), 3.65 (dd, J=3.6, 13.2 Hz, 1H), 3.89 (s,3H), 4.03-4.13 (m, 1H), 4.14-4.24 (m, 1H), 6.92 (brs, 1H), 7.09 (d,J=16.4 Hz, 1H), 7.16-7.35 (m, 8H), 7.58 (d, J=16.4 Hz, 1H), 7.71 (d,J=1.2 Hz, 1H).

Examples 17 and 18 Synthesis of(−)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

230 mg of a racemate of the title compound was obtained from(2-chloropyridyl)-5-acetic acid (500 mg) by the same method as inExamples 1 and 2. The racemate (104 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain a (−)-isomer of the title opticallyactive compound with a retention time of 30 minutes (39 mg; >99% ee) anda (+)-isomer of the title optically active compound with a retentiontime of 54 minutes (38.7 mg; >99% ee).

The property values of(−)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 447 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.94-2.34 (m, 6H),2.36-2.46 (m, 1H), 3.86 (s, 3H), 4.23-4.37 (m, 3H), 6.91 (brs, 1H), 7.03(d, J=16.4 Hz, 1H), 7.10-7.24 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.42-7.54(m, 2H), 7.70 (d, J=1.2 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H).

The property values of(+)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 447 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.94-2.34 (m, 6H),2.36-2.46 (m, 1H), 3.86 (s, 3H), 4.23-4.37 (m, 3H), 6.91 (brs, 1H), 7.03(d, J=16.4 Hz, 1H), 7.10-7.24 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.42-7.54(m, 2H), 7.70 (d, J=1.2 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H).

Example 19 Synthesis of1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-ol

Sodium tetrahydroborate (0.166 mg) was added to a solution of(−)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-oneobtained in Example 3 (2 mg) in methanol (0.5 mL), and the reactionsolution was stirred in a nitrogen atmosphere at room temperature forone hour. Brine and ethyl acetate were added to the reaction solutionand the organic layer was separated. The resulting organic layer wasdried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (carrier: Chromatorex NH; elution solvent: ethylacetate→ethyl acetate:methanol=9:1) to obtain 1.19 mg of the titlecompound.

The property values of1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-olare as follows.

ESI-MS; m/z 498 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 0.89 (t, J=6.8 Hz, 3H),1.10-2.40 (m, 13H), 3.85 (s, 3H), 4.16-4.38 (m, 3H), 4.60-4.70 (m, 1H),6.90 (brs, 1H), 7.01-7.35 (m, 8H), 7.51 (d, J=16.0 Hz, 1H), 7.68 (d,J=1.2 Hz, 1H).

Examples 20 and 21 Synthesis of(−)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-bromophenyl)piperidin-2-one

A solution of ethyl 4-bromophenylacetate (2.0 g) in DMF (5 mL) was addedto a suspension of sodium hydride (containing 40% of mineral oil, 362mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirredfor 10 minutes, further stirred at room temperature for 30 minutes andthen ice-cooled again. A solution of 1-chloro-3-iodopropane (1.85 g) inDMF (5 mL) was added to the reaction mixture, and the reaction solutionwas stirred at room temperature overnight. Water and ethyl acetate wereadded to the reaction mixture and the organic layer was separated. Theresulting organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. Hydrazine monohydrate (8 mL) was added to asolution of the resulting residue in ethanol (20 mL), and the reactionsolution was stirred at room temperature for one day. The reactionmixture was concentrated under reduced pressure. Saturated sodiumbicarbonate water and ethyl acetate and were added to the residue, andthe organic layer was separated. The resulting organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (carrier: Chromatorex NH;elution solvent: heptane-ethyl acetate system) to obtain 898 mg of thetitle compound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.80-2.00 (m, 3H), 2.08-2.15 (m, 1H), 2.14-3.67(m, 3H), 4.62 (s, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H).

Synthesis of(E)-N-[3-(4-bromophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide

BOPCl (1.18 g) was added to a suspension of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (800mg), 1-amino-3-(4-bromophenyl)piperidin-2-one (898 mg) and TEA (0.9 mL)in DMF (20 mL), and the reaction solution was stirred at roomtemperature overnight. Water and ethyl acetate were added to thereaction mixture and the organic layer was separated. The resultingorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (carrier: Chromatorex NH; elution solvent: ethylacetate-methanol system) to obtain 1.484 g of the title compound. Theproperty values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.08 (m, 3H), 2.20-2.26 (m, 1H), 2.30 (s,3H), 3.60-3.66 (m, 1H), 3.74-3.83 (m, 2H), 3.78 (s, 3H), 6.44 (d, J=15.6Hz, 1H), 6.84-6.91 (m, 3H), 7.11 (d, J=8 Hz, 1H), 7.21 (d, J=8.4 Hz,2H), 7.40-7.46 (m, 3H), 7.72 (d, J=1.6 Hz, 1H), 10.22 (s, 1H).

Synthesis of(−)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A solution of(E)-N-[3-(4-bromophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide(1.434 g) in phosphorus oxychloride (6 mL) was heated under reflux forone hour. The reaction mixture was left to cool to room temperature andthen concentrated under reduced pressure. Acetic acid (7 mL) andammonium acetate (4.8 g) were added to the residue, and the reactionsolution was stirred at 150° C. for one hour. The reaction mixture wasleft to cool to room temperature and then concentrated under reducedpressure. Saturated sodium bicarbonate water and ethyl acetate and wereadded to the residue, and the organic layer was separated. The resultingorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (carrier: Chromatorex NH; elution solvent: heptane-ethylacetate system) to obtain 770 mg of a racemate of the title compound.The resulting racemate (73 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: ethanol, flow rate: 10 mL/min) to obtain the title opticallyactive compound with a retention time of 17 minutes and negative opticalrotation (21 mg) and the title optically active compound with aretention time of 20 minutes and positive optical rotation (23 mg).

The property values of the title optically active compound with aretention time of 17 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.26 (m, 3H), 2.30 (s, 3H), 2.32-2.39 (m,1H), 3.86 (s, 3H), 4.27-4.32 (m, 3H), 6.92 (s, 1H), 7.03-7.09 (m, 3H),7.14-7.16 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.51(d, J=16 Hz, 1H), 7.72 (s, 1H).

The property values of the title optically active compound with aretention time of 20 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.26 (m, 3H), 2.30 (s, 3H), 2.32-2.39 (m,1H), 3.86 (s, 3H), 4.27-4.32 (m, 3H), 6.92 (s, 1H), 7.03-7.09 (m, 3H),7.14-7.16 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.51(d, J=16 Hz, 1H), 7.72 (s, 1H).

Examples 22 and 23 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-methoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-methoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of8-(2-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

663 mg of the title compound was obtained from(E)-N-[3-(2-bromophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide(1.130 g) using ethyl 2-bromophenylacetate as a starting material by thesame method as in Examples 20 and 21. The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.20 (m, 3H), 2.30 (s, 3H), 2.35-2.42 (m,1H), 3.86 (s, 3H), 4.25-4.35 (m, 2H), 4.76 (t, J=6.4 Hz, 1H), 6.86 (brd,J=7.6 Hz, 1H), 6.92 (s, 1H), 7.08 (d, J=16.4, 0.8 Hz, 1H), 7.13-7.17 (m,3H), 7.21 (d, J=7.6 Hz, 1H), 7.26-7.27 (m, 2H), 7.51 (dd, J=7.6, 0.8 Hz,1H), 7.69 (d, J=0.8 Hz, 1H).

Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-methoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-methoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Potassium methoxymethyl trifluoroborate (CAS No. 910251-11-5, 372 mg),palladium acetate (7 mg), BINAP (19 mg) and cesium carbonate (1.2 g)were added to a mixed solution of8-(2-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(150 mg) in dioxane (7 mL) and water (0.7 mL). The reaction solution wasstirred in a nitrogen atmosphere at 100° C. overnight. The reactionmixture was left to cool to room temperature. Then, water and ethylacetate were added to the reaction mixture and the organic layer wasseparated. The resulting organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system) and further separated byCHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain thetitle optically active compound with a retention time of 16 minutes andnegative optical rotation (6.2 mg) and the title optically activecompound with a retention time of 18 minutes and positive opticalrotation (8 mg).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.15 (m, 2H), 2.20-2.29 (m, 1H), 2.30 (s,3H), 2.36-2.43 (m, 1H), 3.41 (s, 3H), 3.85 (s, 3H), 4.31 (t, J=5.6 Hz,2H), 4.46 (dd, J=11.6 Hz, 1.6 Hz, 1H), 4.61 (t, J=6.4 Hz, 1H), 4.71 (dd,J=11.6 Hz, 1.6 Hz, 1H), 6.85-6.88 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06(dd, J=16 Hz, 1.6 Hz, 1H), 7.11-7.15 (m, 2H), 7.21 (dd, J=8 Hz, 1.6 Hz,1H), 7.24-7.29 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (dd, J=16 Hz, 1.6 Hz,1H), 7.69 (t, J=1.6 Hz, 1H).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.15 (m, 2H), 2.20-2.29 (m, 1H), 2.30 (s,3H), 2.36-2.43 (m, 1H), 3.41 (s, 3H), 3.85 (s, 3H), 4.31 (t, J=5.6 Hz,2H), 4.46 (dd, J=11.6 Hz, 1.6 Hz, 1H), 4.61 (t, J=6.4 Hz, 1H), 4.71 (dd,J=11.6 Hz, 1.6 Hz, 1H), 6.85-6.88 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06(dd, J=16 Hz, 1.6 Hz, 1H), 7.11-7.15 (m, 2H), 7.21 (dd, J=8 Hz, 1.6 Hz,1H), 7.24-7.29 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (dd, J=16 Hz, 1.6 Hz,1H), 7.69 (t, J=1.6 Hz, 1H).

Examples 24 and 25 Synthesis of (−) and(+)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

559 mg of the title compound was obtained from(E)-N-[3-(2-bromo-4-fluorophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide(953 mg) using methyl 2-bromo-4-fluorophenylacetate as a startingmaterial by the same method as in Examples 20 and 21. The propertyvalues of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.20 (m, 3H), 2.30 (s, 3H), 2.35-2.42 (m,1H), 3.86 (s, 3H), 4.28-4.31 (m, 2H), 4.71 (t, J=6.4 Hz, 1H), 6.87 (dd,J=8.4 Hz, 5.6 Hz, 1H), 6.92 (t, J=1.2 Hz, 1H), 6.96-7.01 (m, 1H), 7.07(d, J=16.4 Hz, 1H), 7.14-7.16 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.36 (dd,J=8.0, 2.8 Hz, 1H), 7.51 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Synthesis of (−) and(+)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

The title optically active compound with a retention time of 15 minutesin CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm, mobile phase: hexane:ethanol=1:1, flow rate: 20 mL/min) andpositive optical rotation (1.1 mg) and the title optically activecompound with a retention time of 25 minutes in the CHIRALPAK™ IB andnegative optical rotation (0.4 mg) were obtained from8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(40 mg) by the same method as in Examples 22 and 23.

The property values of the title optically active compound with aretention time of 15 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.93-2.02 (m, 1H), 2.04-2.14 (m, 1H), 2.18-2.28(m, 1H), 2.29 (s, 3H), 2.32-2.40 (m, 1H), 3.42 (s, 3H), 3.84 (s, 3H),4.30 (t, J=6 Hz, 2H), 4.44 (d, J=12 Hz, 1H), 4.50 (t, J=6 Hz, 1H), 4.65(d, J=12 Hz, 1H), 6.84 (dd, J=8.4 Hz, 5.2 Hz, 1H), 6.90 (s, 1H),6.92-6.97 (m, 1H), 7.04 (d, J=16 Hz, 1H), 7.11-7.14 (m, 3H), 7.20 (d,J=8.0 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 25 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.93-2.02 (m, 1H), 2.04-2.14 (m, 1H), 2.18-2.28(m, 1H), 2.29 (s, 3H), 2.32-2.40 (m, 1H), 3.42 (s, 3H), 3.84 (s, 3H),4.30 (t, J=6 Hz, 2H), 4.44 (d, J=12 Hz, 1H), 4.50 (t, J=6 Hz, 1H), 4.65(d, J=12 Hz, 1H), 6.84 (dd, J=8.4 Hz, 5.2 Hz, 1H), 6.90 (s, 1H),6.92-6.97 (m, 1H), 7.04 (d, J=16 Hz, 1H), 7.11-7.14 (m, 3H), 7.20 (d,J=8.0 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Examples 26 and 27 Synthesis of(−)-2-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrileand(+)-2-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrile

A suspension of8-(2-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(45 mg), zinc cyanide (22 mg) and tetrakistriphenylphosphine palladium(11 mg) in DMF (2 mL) was subjected to microwave reaction in a nitrogenatmosphere at 160° C. for two hours. The reaction mixture was left tocool to room temperature. Then, aqueous ammonia and ethyl acetate wereadded to the reaction mixture and the organic layer was separated. Theresulting organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (carrier: Chromatorex NH; elution solvent:heptane-ethyl acetate system) to obtain 34 mg of a racemate of the titlecompound. The resulting racemate (28 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: ethanol, flow rate: 10 mL/min) to obtain the title opticallyactive compound with a retention time of 17 minutes and negative opticalrotation (11.9 mg) and the title optically active compound with aretention time of 19 minutes and positive optical rotation (13 mg).

The property values of the title optically active compound with aretention time of 17 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.27 (m, 3H), 2.31 (s, 3H), 2.47-2.53 (m,1H), 3.86 (s, 3H), 4.30-4.37 (m, 2H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H),6.92 (s, 1H), 7.06 (d, J=16 Hz, 1H), 7.13-7.17 (m, 3H), 7.22 (d, J=8 Hz,1H), 7.26-7.31 (m, 2H), 7.42 (dd, J=8 Hz, 2.8 Hz, 1H), 7.48 (d, J=16 Hz,1H), 7.73 (s, 1H).

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.27 (m, 3H), 2.31 (s, 3H), 2.47-2.53 (m,1H), 3.86 (s, 3H), 4.30-4.37 (m, 2H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H),6.92 (s, 1H), 7.06 (d, J=16 Hz, 1H), 7.13-7.17 (m, 3H), 7.22 (d, J=8 Hz,1H), 7.26-7.31 (m, 2H), 7.42 (dd, J=8 Hz, 2.8 Hz, 1H), 7.48 (d, J=16 Hz,1H), 7.73 (s, 1H).

Examples 28 and 29 Synthesis of5-fluoro-2-{(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrileand5-fluoro-2-{(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrile

The title optically active compound with a retention time of 17 minutesin CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm, mobile phase: hexane:ethanol=9:1, flow rate: 20 mL/min) andnegative optical rotation (9.5 mg) and the title optically activecompound with a retention time of 23 minutes in the CHIRALPAK™ IB andpositive optical rotation (9.4 mg) were obtained from8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(40 mg) by the same method as in Examples 26 and 27.

The property values of the title optically active compound with aretention time of 17 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.09 (m, 1H), 2.16-2.27 (m, 2H), 2.30 (s,3H), 2.46-2.53 (m, 1H), 3.86 (s, 3H), 4.27-4.39 (m, 2H), 4.66 (dd, J=8.8Hz, 6 Hz, 1H), 6.92 (s, 1H), 7.06 (d, J=16 Hz, 1H), 7.13-7.16 (m, 3H),7.22 (d, J=7.6 Hz, 1H), 7.30 (dd, J=8 Hz, 2.8 Hz, 1H), 7.42 (dd, J=8 Hz,2.8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.73 (s, 1H).

The property values of the title optically active compound with aretention time of 23 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.09 (m, 1H), 2.16-2.27 (m, 2H), 2.30 (s,3H), 2.46-2.53 (m, 1H), 3.86 (s, 3H), 4.27-4.39 (m, 2H), 4.66 (dd, J=8.8Hz, 6 Hz, 1H), 6.92 (s, 1H), 7.06 (d, J=16 Hz, 1H), 7.13-7.16 (m, 3H),7.22 (d, J=7.6 Hz, 1H), 7.30 (dd, J=8 Hz, 2.8 Hz, 1H), 7.42 (dd, J=8 Hz,2.8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.73 (s, 1H).

Examples 30 and 31 Synthesis of(−)-8-(4-fluoro-2-pyridin-3-yl-phenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-phenyl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(4-fluoro-2-pyridin-3-yl-phenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-phenyl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Pyridine-3-borane acid (18.1 mg), tetrakis(triphenylphosphine)palladium(5.7 mg) and a 2 M sodium carbonate solution (197 μl) in toluene (1.2ml)/ethanol (0.3 ml) were added to8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(50 mg) as a starting material, and the reaction solution was stirred at100° C. for two hours. Thereafter, tetrakis(triphenylphosphine)palladium(17.0 mg) was added and the reaction solution was stirred for 16 hours.The reaction solution was diluted with ethyl acetate and the organiclayer was washed with brine. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 15.4 mg of aracemate of the title compound. The resulting racemate (15.4 mg) wasseparated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries,Ltd. (2 cm×cm, mobile phase: hexane:ethanol=3:7, flow rate: 20 mL/min)to obtain the title optically active compound with a retention time of31 minutes and negative optical rotation (5.0 mg) and the titleoptically active compound with a retention time of 41 minutes andpositive optical rotation (4.7 mg).

The property values of the title optically active compound with aretention time of 31 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.80-2.20 (m, 4H), 2.30 (s, 3H), 3.86 (s, 3H),4.05-4.30 (m, 3H), 6.90 (s, 1H), 7.00-7.05 (m, 1H), 7.05 (d, J=16.0 Hz,1H), 7.10-7.20 (m, 2H), 7.25-7.45 (m, 3H), 7.50 (d, J=16.0 Hz, 1H), 7.70(d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.70 (d, J=4.8Hz, 1H), 8.80 (brd-s, 1H).

The property values of the title optically active compound with aretention time of 41 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.80-2.20 (m, 4H), 2.30 (s, 3H), 3.86 (s, 3H),4.05-4.30 (m, 3H), 6.90 (s, 1H), 7.00-7.05 (m, 1H), 7.05 (d, J=16.0 Hz,1H), 7.10-7.20 (m, 2H), 7.25-7.45 (m, 3H), 7.50 (d, J=16.0 Hz, 1H), 7.70(d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.70 (d, J=4.8Hz, 1H), 8.80 (brd-s, 1H).

Examples 32 and 33 Synthesis of2-((−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamineand2-((+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-nitrophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

The title compound (920 mg) was obtained from(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[3-(2-nitrophenyl)-2-oxopiperidin-1-yl]acrylamide(1.279 g) using methyl 2-nitrophenylacetate as a starting material bythe same method as in Examples 20 and 21. The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.13-2.32 (m, 3H), 2.29 (s, 3H), 2.55-2.61 (m,1H), 3.85 (s, 3H), 4.31-4.35 (m, 2H), 4.92-4.95 (m, 1H), 6.91-6.92 (m,1H), 7.04 (d, J=16.4 Hz, 1H), 7.12-7.14 (m, 3H), 7.21 (d, J=7.6 Hz, 1H),7.43-7.49 (m, 2H), 7.56-7.60 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 8.03 (dd,J=8.0, 1.6 Hz, 1H).

Synthesis of2-((−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamineand2-((+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine

A mixed solution of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-nitrophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(178 mg) and sodium dithionite (340 mg) in ethanol (10 mL) and water (2mL) was stirred at room temperature for one hour. Water and ethylacetate were added to the reaction mixture and the organic layer wasseparated. The resulting organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system) to obtain 70 mg of a racemate ofthe title compound. The resulting racemate (30 mg) was separated byCHIRALPAK™ ADH manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain the titleoptically active compound with a retention time of 17 minutes andnegative optical rotation (12.7 mg) and the title optically activecompound with a retention time of 28 minutes and positive opticalrotation (13.2 mg).

The property values of the title optically active compound with aretention time of 17 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.10-2.18 (m, 1H), 2.24-2.34 (m, 3H), 2.30 (s,3H), 3.87 (s, 3H), 4.03 (brs, 2H), 4.26-2.30 (m, 2H), 4.36 (t, J=5.6 Hz,1H), 6.77-6.81 (m, 2H), 6.88 (dd, J=7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J=1.6Hz, 1H), 7.05 (d, J=16 Hz, 1H), 7.10-7.15 (m, 3H), 7.22 (d, J=7.6 Hz,1H), 7.50 (d, J=16 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 28 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.10-2.18 (m, 1H), 2.24-2.34 (m, 3H), 2.30 (s,3H), 3.87 (s, 3H), 4.03 (brs, 2H), 4.26-2.30 (m, 2H), 4.36 (t, J=5.6 Hz,1H), 6.77-6.81 (m, 2H), 6.88 (dd, J=7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J=1.6Hz, 1H), 7.05 (d, J=16 Hz, 1H), 7.10-7.15 (m, 3H), 7.22 (d, J=7.6 Hz,1H), 7.50 (d, J=16 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Examples 34 and 35 Synthesis ofN-[2-((−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ylphenyl]acetamideandN-[2-((+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ylphenyl]acetamide

Acetic anhydride (0.045 mL) was added to a solution of2-((−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine(41 mg) in pyridine (2 mL), and the reaction solution was stirred at 50°C. overnight. The reaction mixture was left to cool to room temperatureand then concentrated under reduced pressure. The resulting residue waspurified by CHIRALPAK™ IB manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtainthe title optically active compound with a retention time of 11 minutesand negative optical rotation (14.9 mg) and the title optically activecompound with a retention time of 14 minutes and positive opticalrotation (15.1 mg).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.20-2.28 (m, 1H), 2.23 (s, 3H), 2.30 (s, 3H),2.32-2.48 (m, 3H), 3.89 (s, 3H), 4.24-4.32 (m, 2H), 4.37 (t, J=6 Hz,1H), 6.93 (t, J=1.2 Hz, 1H), 7.01 (d, J=16 Hz, 1H), 7.14-7.16 (m, 2H),7.19-7.25 (m, 2H), 7.29-7.39 (m, 2H), 7.45 (d, J=16 Hz, 1H), 7.72-7.75(m, 2H), 9.87 (s, 1H).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.20-2.28 (m, 1H), 2.23 (s, 3H), 2.30 (s, 3H),2.32-2.48 (m, 3H), 3.89 (s, 3H), 4.24-4.32 (m, 2H), 4.37 (t, J=6 Hz,1H), 6.93 (t, J=1.2 Hz, 1H), 7.01 (d, J=16 Hz, 1H), 7.14-7.16 (m, 2H),7.19-7.25 (m, 2H), 7.29-7.39 (m, 2H), 7.45 (d, J=16 Hz, 1H), 7.72-7.75(m, 2H), 9.87 (s, 1H).

Examples 36 and 37 Synthesis of(−)-8-(3,4-dimethoxyphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3,4-dimethoxyphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

559 mg of the title compound was obtained from(E)-N-[3-(3,4-dimethoxyphenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide(401 mg) using ethyl 3,4-dimethoxyphenylacetate as a starting materialby the same method as in Examples 20 and 21. The resulting racemate (77mg) was separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to obtain the title optically active compound with a retentiontime of 24 minutes and negative optical rotation (17.8 mg) and the titleoptically active compound with a retention time of 31 minutes andpositive optical rotation (19.0 mg).

The property values of the title optically active compound with aretention time of 24 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.20-2.14 (m, 2H), 2.18-2.27 (m, 1H), 2.30 (s,3H), 2.31-2.38 (m, 1H), 3.86 (s, 6H), 3.87 (s, 3H), 4.23-4.36 (m, 3H),6.64 (dd, J=8.4 Hz, 1.6 Hz, 1H), 6.71 (d, J=1.6 Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 6.91 (q, J=1.2 Hz, 1H), 7.08 (dd, J=16.4 Hz, 0.8 Hz, 1H),7.13-7.16 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.70(s, 1H).

The property values of the title optically active compound with aretention time of 31 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.20-2.14 (m, 2H), 2.18-2.27 (m, 1H), 2.30 (s,3H), 2.31-2.38 (m, 1H), 3.86 (s, 6H), 3.87 (s, 3H), 4.23-4.36 (m, 3H),6.64 (dd, J=8.4 Hz, 1.6 Hz, 1H), 6.71 (d, J=1.6 Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 6.91 (q, J=1.2 Hz, 1H), 7.08 (dd, J=16.4 Hz, 0.8 Hz, 1H),7.13-7.16 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.70(s, 1H).

Examples 38 and 39 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

208.5 mg of a racemate of the title compound was obtained from methyl2-pyridylacetate (6.76 g) by the same method as in Examples 20 and 21.The racemate (100 mg) was separated by CHIRALCEL™ OD-H manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) toobtain a (−)-isomer of the title optically active compound with aretention time of 17 minutes (43.6 mg; 79% ee) and a (+)-isomer of thetitle optically active compound with a retention time of 24 minutes(47.7 mg; 87% ee).

The property values of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 413 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.17 (m, 1H),2.19-2.46 (m, 6H), 3.85 (s, 3H), 4.20-4.37 (m, 2H), 4.48 (t, J=6.4 Hz,1H), 6.90 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.4 Hz, 1H), 7.10-7.24 (m, 5H),7.49 (d, J=16.4 Hz, 1H), 7.62-7.72 (m, 2H), 8.57 (dd, J=2.4, 5.6 Hz,1H).

The property values of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 413 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.17 (m, 1H),2.19-2.46 (m, 6H), 3.85 (s, 3H), 4.20-4.37 (m, 2H), 4.48 (t, J=6.4 Hz,1H), 6.90 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.4 Hz, 1H), 7.10-7.24 (m, 5H),7.49 (d, J=16.4 Hz, 1H), 7.62-7.72 (m, 2H), 8.57 (dd, J=2.4, 5.6 Hz,1H).

Examples 40 and 41 Synthesis of(−)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of ethyl (5-chlorothiophen-2-yl)acetate

Methyl methylsulfinylmethyl sulfide (5.53 g) and potassium hydroxide (2g) were added to a solution of 5-chloro-2-thiophenecarboxyaldehyde (6.21g) in methanol (70 mL), and the reaction solution was stirred withheating under reflux for 21 hours. After leaving to cool to roomtemperature, the solvent was evaporated under reduced pressure.Methylene chloride was added to the residue, the insoluble matter wasremoved by filtration, and the solvent was evaporated under reducedpressure. Then, the residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain5.61 g of a (E)/(Z) mixture of2-chloro-5-(2-methanesulfinyl-2-methylsulfanylvinyl)thiophene. Asaturated solution of hydrogen chloride in ethanol (10 mL) was added toa solution of the resulting (E)/(Z) mixture of2-chloro-5-(2-methanesulfinyl-2-methylsulfanylvinyl)thiophene (5.61 g)in ethanol (80 mL), and the reaction solution was stirred with heatingunder reflux for 23 hours. After leaving to cool to room temperature,the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 3.31 g of the title compound.The property values of the compound are as follows.

ESI-MS; m/z 205 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.28 (t, J=7.2 Hz, 3H),3.72 (d, J=0.8 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 6.67-6.71 (m, 1H), 6.75(d, J=3.6 Hz, 1H).

Synthesis of(−)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

5.2 mg of a racemate of the title compound was obtained from ethyl(5-chlorothiophen-2-yl)acetate (3.31 g) by the same method as inExamples 20 and 21. The racemate (5.2 mg) was separated by CHIRALPAK™ IAmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain a (−)-isomer of the title opticallyactive compound with a retention time of 11.5 minutes (1.08 mg; >99% ee)and a (+)-isomer of the title optically active compound with a retentiontime of 24 minutes (0.74 mg; >99% ee).

The property values of(−)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 452 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.03-2.22 (m, 2H),2.23-2.36 (m, 4H), 2.37-2.47 (m, 1H), 3.86 (s, 3H), 4.29 (t, J=5.6 Hz,2H), 4.74 (t, J=7.6 Hz, 1H), 6.92 (brs, 1H), 6.94 (d, J=5.6 Hz, 1H),7.07 (d, J=16.4 Hz, 1H), 7.12-7.24 (m, 4H), 7.53 (d, J=16.4 Hz, 1H),7.71 (brs, 1H).

The property values of(+)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineare as follows.

ESI-MS; m/z 452 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.03-2.22 (m, 2H),2.23-2.36 (m, 4H), 2.37-2.47 (m, 1H), 3.86 (s, 3H), 4.29 (t, J=5.6 Hz,2H), 4.74 (t, J=7.6 Hz, 1H), 6.92 (brs, 1H), 6.94 (d, J=5.6 Hz, 1H),7.07 (d, J=16.4 Hz, 1H), 7.12-7.24 (m, 4H), 7.53 (d, J=16.4 Hz, 1H),7.71 (brs, 1H).

The following compounds were obtained by the same method as in Examples20 and 21 (Table 1).

TABLE 1

Example E₁ E2 DATA: MS m/z Note 42

H M⁺ + H: 463 (ESI) Optically active compound (separation conditionsOD-H: retention time 36 min, optical rotation (−)) 43

H M⁺ + H: 463 (ESI) Optically active compound (separation conditionsOD-H: retention time 46 min, optical rotation (+)) 44

H M⁺ + H: 480 (ESI) Optically active compound (separation conditionsAD-H: retention time 33 min, optical rotation (+)) 45

H M⁺ + H: 480 (ESI) Optically active compound (separation conditionsAD-H: retention time 47 min, optical rotation (−)) 46

H M⁺ + H: 430 (ESI) Optically active compound (separation conditions 80%ethanol-hexane:IB: retention time 15 min, optical rotation (+)) 47

H M⁺ + H: 430 (ESI) Optically active compound (separation conditions 80%ethanol-hexane:IB: retention time 27 min, optical rotation (−)) 48

H M⁺ + H: 448 (ESI) 49

H M⁺ + H: 448 (ESI) 50

H M⁺ + H: 464 (ESI) 51

H M⁺ + H: 466 (ESI) 52

H M⁺ + H: 466 (ESI)

Examples 53 and 54 Synthesis of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

Sodium hydride (containing 40% of mineral oil, 21 mg) was added to asolution of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridinesynthesized by the method in Example 38 and 39 (108 mg) in DMF (1.2 mL),and the reaction solution was stirred at room temperature for threehours under oxygen bubbling. Sodium thiosulfate pentahydride was addedto the reaction solution, and the reaction solution was stirred at roomtemperature for several minutes. Ethyl acetate and a saturated ammoniumchloride solution were added to the reaction solution and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain the racemic title compound.

The racemate of the title compound was separated by CHIRALPAK™ IAmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain a (+)-isomer of the title optically activecompound with a retention time of 11 minutes (49.3 mg, >99% ee) and a(−)-isomer of the title optically active compound with a retention timeof 13 minutes (44.6 mg, 94% ee).

The property values of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

ESI-MS; m/z 429 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.11-2.37 (m, 6H),2.50-2.64 (m, 1H), 3.81 (s, 3H), 4.22-4.32 (m, 1H), 4.35-4.44 (m, 1H),6.88 (brs, 1H), 6.96-7.10 (m, 3H), 7.16 (d, J=8.0 Hz, 1H), 7.24-7.38 (m,2H), 7.43 (d, J=16.4 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (dt, J=1.2,8.0 Hz, 1H), 8.54-8.62 (m, 1H).

The property values of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

ESI-MS; m/z 429 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.11-2.37 (m, 6H),2.50-2.64 (m, 1H), 3.81 (s, 3H), 4.22-4.32 (m, 1H), 4.35-4.44 (m, 1H),6.88 (brs, 1H), 6.96-7.10 (m, 3H), 7.16 (d, J=8.0 Hz, 1H), 7.24-7.38 (m,2H), 7.43 (d, J=16.4 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (dt, J=1.2,8.0 Hz, 1H), 8.54-8.62 (m, 1H).

Examples 55 and 56 Synthesis of(−)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

A racemate of title compound (67.1 mg) was obtained from8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridinesynthesized in Examples 5 and 6 (117.4 mg) by the same method as inExamples 53 and 54. The racemate of the title compound was separated byCHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain a (−)-isomer ofthe title optically active compound with a retention time of 13.5minutes (20.7 mg; >99% ee) and a (+)-isomer of the title opticallyactive compound with a retention time of 16.5 minutes (20.1 mg; 98% ee).

The property values of(−)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

ESI-MS; m/z 470 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.23 (d, J=6.8 Hz, 6H),1.92-2.05 (m, 1H), 2.21-2.40 (m, 6H), 2.84-2.96 (m, 1H), 3.82 (s, 3H),4.25 (t, J=5.6 Hz, 2H), 6.89 (brs, 1H), 7.02-7.13 (m, 3H), 7.14-7.24 (m,5H), 7.49 (d, J=16.4 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

ESI-MS; m/z 470 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.23 (d, J=6.8 Hz, 6H),1.92-2.05 (m, 1H), 2.21-2.40 (m, 6H), 2.84-2.96 (m, 1H), 3.82 (s, 3H),4.25 (t, J=5.6 Hz, 2H), 6.89 (brs, 1H), 7.02-7.13 (m, 3H), 7.14-7.24 (m,5H), 7.49 (d, J=16.4 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Examples 57 and 58 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

59 mg of the title compound was obtained from ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (650 mg) and 5-chloro-2-phenylpentanoic acid hydrazide(436 mg) by the same method as in Example 1. The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.12 (m, 2H), 2.16-2.24 (m, 1H), 2.29 (s,3H), 2.33-2.40 (m, 1H), 3.85 (s, 3H), 4.21-4.37 (m, 3H), 6.91 (s, 1H),7.07 (d, J=16.4 Hz, 1H), 7.13-7.15 (m, 3H), 7.21 (d, J=7.6 Hz, 1H),7.26-7.29 (m, 2H), 7.32-7.36 (m, 2H), 7.52 (d, J=16.4 Hz, 1H), 7.69 (s,1H).

Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol

The title optically active compound with a retention time of 14 minutesin CHIRALPAK™ ADH manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) and negativeoptical rotation (9.5 mg) and the title optically active compound with aretention time of 16 minutes in the CHIRALPAK™ ADH and positive opticalrotation (9.4 mg) were obtained from2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(59 mg) by the same method as in Examples 53 and 54.

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.95-2.03 (m, 1H), 2.21-2.27 (m, 1H), 2.28 (s,3H), 2.31-2.38 (m, 2H), 3.81 (s, 3H), 4.25 (t, J=6 Hz, 2H), 6.88 (s,1H), 7.00-7.07 (m, 3H), 7.16 (d, J=8 Hz, 1H), 7.29-7.35 (m, 5H), 7.46(d, J=16.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.95-2.03 (m, 1H), 2.21-2.27 (m, 1H), 2.28 (s,3H), 2.31-2.38 (m, 2H), 3.81 (s, 3H), 4.25 (t, J=6 Hz, 2H), 6.88 (s,1H), 7.00-7.07 (m, 3H), 7.16 (d, J=8 Hz, 1H), 7.29-7.35 (m, 5H), 7.46(d, J=16.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).

Examples 59 and 60 Synthesis of(−)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol

Synthesis of8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

468 mg of the title compound was obtained from(E)-N-[3-(2-fluorophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide(761 mg) using methyl 2-fluorophenylacetate as a starting material bythe same method as in Examples 20 and 21. The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.24 (m, 3H), 2.29 (s, 3H), 2.33-2.39 (m,1H), 3.85 (s, 3H), 4.27-4.30 (m, 2H), 4.58-4.61 (m, 1H), 6.91-6.92 (m,1H), 6.93-6.98 (m, 1H), 7.05-7.15 (m, 5H), 7.21 (d, J=7.6 Hz, 1H),7.24-7.30 (m, 1H), 7.51 (d, J=16.4 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol

The title optically active compound with a retention time of 12 minutesin CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) and positiveoptical rotation (20.6 mg) and the title optically active compound witha retention time of 14 minutes in the CHIRALPAK™ IA and negative opticalrotation (17.2 mg) were obtained from8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(50 mg) by the same method as in Examples 53 and 54.

The property values of the title optically active compound with aretention time of 12 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.11 (m, 1H), 2.22-2.36 (m, 2H), 2.30 (s,3H), 3.76 (s, 3H), 4.13-4.20 (m, 1H), 4.29-4.35 (m, 1H), 6.85-6.99 (m,4H), 7.09 (d, J=8 Hz, 2H), 7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H), 7.34(d, J=18.8 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 7.83-7.88 (m, 1H).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.11 (m, 1H), 2.22-2.36 (m, 2H), 2.30 (s,3H), 3.76 (s, 3H), 4.13-4.20 (m, 1H), 4.29-4.35 (m, 1H), 6.85-6.99 (m,4H), 7.09 (d, J=8 Hz, 2H), 7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H), 7.34(d, J=18.8 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 7.83-7.88 (m, 1H).

The following compounds were obtained by the same method as in Examples53 and 54 (Table 2).

TABLE 2

Example E₁ E2 DATA: MS m/z Note 61

OH M⁺ + H: 496 (ESI) Optically active compound (separation conditionsIA: retention time 21 min, optical rotation (−)) 62

OH M⁺ + H: 496 (ESI) Optically active compound (separation conditionsIA: retention time 29 min, optical rotation (+)) 63

OH M⁺ + H: 479 (ESI) Optically active compound (separation conditionsAD-H: retention time 15 min optical rotation (−)) 64

OH M⁺ + H: 479 (ESI) Optically active compound (separation conditionsAD-H: retention time 21 min optical rotation (+))

Examples 65 and 66 Synthesis of(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileand(−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

Synthesis of(8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol

Paraformaldehyde (186 mg) and sodium hydride (containing 40% of mineraloil, 28.7 mg) were added to a solution of8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridinesynthesized by the method in Examples 1 and 2 (154 mg) in DMF (3 mL),and the reaction solution was stirred at room temperature for 30minutes. Thereafter, ethyl acetate and saturated sodium bicarbonatewater were added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtain 204mg of the title compound. The property value of the compound is asfollows.

ESI-MS; m/z 460 [M⁺+H].

Synthesis of8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde

Dess-Martin periodinane (304 mg) was added to a solution of(8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol(165 mg) in methylene chloride (10 mL), and the reaction solution wasstirred in a nitrogen atmosphere at room temperature for four hours.Ethyl acetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 227 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 458 [M⁺+H].

Synthesis of8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehydeoxime

Sodium acetate (58.7 mg) and hydroxylammonium chloride (49.8 mg) wereadded to a solution of8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde(164 mg) in ethanol (10 mL), and the reaction solution was stirred atroom temperature for five hours. Ethyl acetate and saturated sodiumbicarbonate water were added to the reaction solution and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reduced pressureto obtain 169 mg of the title compound. The property value of thecompound is as follows.

ESI-MS; m/z 473 [M⁺+H].

Synthesis of(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileand(−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

1,1-Carbonylbis-1H-imidazole (290 mg) was added to a solution of8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehydeoxime (169 mg) in THF (15 mL), and the mixture was heated under refluxfor 2.5 hours. The reaction solution was cooled to room temperature.Then, ethyl acetate and brine were added to the reaction solution andthe organic layer was separated. The resulting organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(carrier: Chromatorex NH; elution solvent: heptane:ethylacetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) to obtain 84.6 mgof a racemate of the title compound. The resulting racemate (84.6 mg)was separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) toobtain a (+)-isomer of the title optically active compound with aretention time of 14 minutes (26.5 mg; >99% ee) and a (−)-isomer of thetitle optically active compound with a retention time of 17 minutes(25.1 mg; 98% ee).

The property values of(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileare as follows.

ESI-MS; m/z 455 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.12-2.25 (m, 1H),2.26-2.51 (m, 5H), 2.67-2.77 (m, 1H), 3.87 (s, 3H), 4.26-4.42 (m, 2H),6.92 (t, J=1.2 Hz, 1H), 6.99-7.27 (m, 7H), 7.37-7.44 (m, 1H), 7.58 (d,J=16.0 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H).

The property values of(−)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileare as follows.

ESI-MS; m/z 455 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.12-2.25 (m, 1H),2.26-2.51 (m, 5H), 2.67-2.77 (m, 1H), 3.87 (s, 3H), 4.26-4.42 (m, 2H),6.92 (t, J=1.2 Hz, 1H), 6.99-7.27 (m, 7H), 7.37-7.44 (m, 1H), 7.58 (d,J=16.0 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H).

Examples 67 and 68 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

62 mg of a racemate of the title compound was obtained by the samemethod as in Examples 65 and 66 from2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained by the method in Examples 28 and 29 (135.6 mg). The racemate(62 mg) was separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain a(−)-isomer of the title optically active compound with a retention timeof 23 minutes (13.9 mg; >99% ee) and a (+)-isomer of the title opticallyactive compound with a retention time of 32.5 minutes (15.3 mg; >99%ee).

The property values of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileare as follows.

ESI-MS; m/z 483 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.12-2.24 (m, 1H),2.28-2.54 (m, 8H), 2.64-2.74 (m, 1H), 3.86 (s, 3H), 4.26-4.40 (m, 2H),6.91 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.13-7.30 (m, 7H), 7.57(d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

The property values of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileare as follows.

ESI-MS; m/z 483 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.12-2.24 (m, 1H),2.28-2.54 (m, 8H), 2.64-2.74 (m, 1H), 3.86 (s, 3H), 4.26-4.40 (m, 2H),6.91 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.13-7.30 (m, 7H), 7.57(d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Examples 69 and 70 Synthesis of(−)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}methanoland(+)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}methanol

Synthesis of tert-butylN′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate andtert-butylN′-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

IPEA (1.7 mL), HOBT (851 mg) and EDC (1.2 g) were added to a solution of5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid (840 mg) synthesizedaccording to the method described in Tetrahedron Letters, 2003, vol. 44,p. 365 and tert-butyl carbazate (500 mg) in DMF (5 mL), and the reactionsolution was stirred at room temperature for 23 hours. Ethyl acetate andsaturated sodium bicarbonate water were added to the reaction solution,and the organic layer was separated. The resulting organic layer wasdried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane→heptane:ethyl acetate=1:1) toobtain 718 mg of tert-butylN′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate and420 mg of tert-butylN′-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate.

The property values of tert-butylN′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate areas follows.

ESI-MS; m/z 403 [M⁺+Na]. ¹H-NMR (CDCl₃) δ (ppm): 1.45 (s, 9H), 1.64-2.00(m, 3H), 2.15-2.26 (m, 1H), 3.30 (t, J=7.2 Hz, 1H), 3.47-3.60 (m, 2H),6.99 (dd, J=8.4, 6.4 Hz, 2H).

The property value of tert-butylN′-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylateis as follows.

ESI-MS; m/z 480 [M⁺+H].

Synthesis oftert-butyl[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]carbamate

Sodium iodide (131 mg) and sodium hydride (containing 40% of mineraloil, 70 mg) were added to a solution of tert-butylN′-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(420 mg) in DMF (3 mL), and the reaction solution was stirred at 100° C.for 19 hours. The reaction solution was left to cool to roomtemperature. Ethyl acetate and saturated sodium bicarbonate water wereadded to the reaction solution, and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: heptane→ethylacetate) to obtain 134 mg of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CD₃OD) δ (ppm): 1.50 (s, 9H), 1.90-2.05 (m, 3H), 2.15-2.23 (m,1H), 3.61-3.80 (m, 3H), 6.70 (brs, 1H), 6.90 (t, J=8.0, 6.8 Hz, 2H).

Synthesis of 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-onehydrochloride

A solution of 4 N hydrochloric acid in ethyl acetate (1 mL) was added toa solution of tert-butyl[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]carbamate (134 mg) inchloroform (1 mL), and the reaction solution was stirred at roomtemperature for three hours. The reaction solution was concentratedunder reduced pressure to obtain 109 mg of the title compound. Theproperty value of the compound is as follows.

ESI-MS; m/z 245 [M⁺+H].

Synthesis of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]acrylamide

IPEA (0.41 mL), HOBT (105 mg) and EDC (149 mg) were added to a solutionof 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one hydrochloride (109mg) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylicacid (100 mg) in DMF (2 mL), and the reaction solution was stirred atroom temperature for three hours. Ethyl acetate and saturated sodiumbicarbonate water were added to the reaction solution, and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 95mg of the title compound. The property values of the compound are asfollows.

ESI-MS; m/z 485 [M⁺+H]. ¹H-NMR (CD₃OD) δ (ppm): 1.94-2.10 (m, 3H),2.22-2.30 (m, 1H), 2.31 (s, 3H), 3.64-3.72 (m, 1H), 3.78-3.82 (m, 2H),3.84 (s, 3H), 6.41 (d, J=16.0 Hz, 1H), 6.88 (brd, J=8.0 Hz, 1H), 6.90(brs, 1H), 6.93 (s, 1H), 7.00 (dd, J=6.8, 3.6 Hz, 2H), 7.14 (d, J=8.0Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 9.87 (brs,1H).

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]acrylamide(95 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for onehour. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. Ammonium acetate (302 mg) wasadded to a solution of the residue in acetic acid (1 mL), and thereaction solution was stirred at 150° C. for three hours. The reactionsolution was left to cool to room temperature. Then, ethyl acetate andsaturated sodium bicarbonate water were added to the reaction solution,and the organic layer was separated. The resulting organic layer wasdried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex NH; elution solvent: heptane:ethylacetate=1:1→ethyl acetate) to obtain 50 mg of a racemate of the titlecompound. The property values of the compound are as follows.

ESI-MS; m/z 466 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.97-2.25 (m, 3H), 2.30(s, 3H), 2.32-2.42 (m, 1H), 3.86 (s, 3H), 4.24-4.30 (m, 3H), 6.82 (dd,J=8.0, 6.0 Hz, 2H), 6.91 (brs, 1H), 7.05 (d, J=16.8 Hz, 1H), 7.14 (dd,J=8.4, 1.6 Hz, 1H), 7.16 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.50 (d,J=16.8 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Synthesis of(−)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}methanoland(+)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}methanol

Sodium hydride (40% oil suspension, 31 mg) was added to a solution of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(180 mg) and paraformaldehyde (200 mg) in DMF (3 mL), and the reactionsolution was stirred at room temperature for 30 minutes. Ethyl acetateand saturated sodium bicarbonate water were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure to obtain 194 mg of a racemic crude product. Theresulting racemate (40 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase:hexane:ethanol=7:3) to obtain the title optically active compound with aretention time of 9 minutes and negative optical rotation (10 mg) andthe title optically active compound with a retention time of 11 minutesand positive optical rotation (10 mg).

The property values of the title optically active compound with aretention time of 9 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.84-1.97 (m, 1H), 2.05-2.16 (m, 2H), 2.21-2.29(m, 1H), 2.30 (s, 3H), 3.89 (s, 3H), 3.89 (d, J=11.6 Hz, 1H), 4.08 (d,J=11.6 Hz, 1H), 4.10 (td, J=13.2, 6.0 Hz, 1H), 4.30 (dd, J=13.2, 6.0 Hz,1H), 6.80 (dd, J=8.8, 6.4 Hz, 2H), 6.92 (brs, 1H), 7.07 (d, J=16.4 Hz,1H), 7.16 (brs, 1H), 7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (d, J=8.0 Hz,1H), 7.57 (d, J=16.4 Hz, 1H), 7.72 (brs, 1H).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.84-1.97 (m, 1H), 2.05-2.16 (m, 2H), 2.21-2.29(m, 1H), 2.30 (s, 3H), 3.89 (s, 3H), 3.89 (d, J=11.6 Hz, 1H), 4.08 (d,J=11.6 Hz, 1H), 4.10 (td, J=13.2, 6.0 Hz, 1H), 4.30 (dd, J=13.2, 6.0 Hz,1H), 6.80 (dd, J=8.8, 6.4 Hz, 2H), 6.92 (brs, 1H), 7.07 (d, J=16.4 Hz,1H), 7.16 (brs, 1H), 7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (d, J=8.0 Hz,1H), 7.57 (d, J=16.4 Hz, 1H), 7.72 (brs, 1H).

Examples 71 and 72 Synthesis of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileand(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

Dess-Martin periodinane (190 mg) was added to a solution of the crudeproduct of{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}methanolobtained in Examples 69 and 70 (111 mg) in methylene chloride (8 mL),and the reaction solution was stirred at room temperature for 10 hours.Ethyl acetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. Sodium acetate (35 mg) andhydroxyamine hydrochloride (30 mg) were added to a solution of theresidue in ethanol (7 mL), and the reaction solution was stirred at roomtemperature for four hours. Ethyl acetate and saturated sodiumbicarbonate water were added to the reaction solution, and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. CDI (180 mg) was added to a solution of the residue in THF (13mL), and the reaction solution was heated under reflux for one hour. Thereaction solution was left to cool to room temperature. Then, ethylacetate and brine were added to the reaction solution, and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting racemic crude product was separated byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: hexane:ethanol=1:1) to obtain the title opticallyactive compound with a retention time of 11 minutes and negative opticalrotation (38 mg) and the title optically active compound with aretention time of 15 minutes and positive optical rotation (40 mg).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.20-2.29 (m, 1H), 2.30 (s, 3H), 2.35-2.50 (m,2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H), 4.26-4.34 (m, 1H), 4.36-4.44 (m,1H), 6.92 (brs, 1H), 7.04 (d, J=16.8 Hz, 1H), 7.05 (dd, J=7.6, 6.4 Hz,2H), 7.16 (brs, 1H), 7.17 (brd, J=7.2 Hz, 1H), 7.24 (d, J=7.2 Hz, 1H),7.56 (d, J=16.8 Hz, 1H), 7.70 (brs, 1H).

The property values of the title optically active compound with aretention time of 15 minutes corresponded to the property values of thetitle optically active compound with a retention time of 11 minutes.

Examples 73 and 74 Synthesis of(+)-8-(4-chlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileand(−)-8-(4-chlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

A racemate of the title compound obtained from8-(4-chlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(197 mg) by the same method as in Examples 65 and 66 was separated byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: ethanol) to obtain the title optically active compoundwith a retention time of 16 minutes and positive optical rotation (40mg) and the title optically active compound with a retention time of 18minutes and negative optical rotation (47 mg).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.13-2.25 (m, 1H), 2.30 (s, 3H), 2.32-2.47 (m,2H), 2.66-2.75 (m, 1H), 3.87 (s, 3H), 4.28-4.42 (m, 2H), 6.93 (brs, 1H),7.06 (d, J=16.0 Hz, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.18 (dd, J=8.4, 1.6Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8Hz, 2H), 7.57 (d, J=16.0 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.13-2.25 (m, 1H), 2.30 (s, 3H), 2.32-2.47 (m,2H), 2.66-2.75 (m, 1H), 3.87 (s, 3H), 4.28-4.42 (m, 2H), 6.93 (brs, 1H),7.06 (d, J=16.0 Hz, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.18 (dd, J=8.4, 1.6Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8Hz, 2H), 7.57 (d, J=16.0 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).

Examples 75 and 76 Synthesis of(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrileand(−)-8-(3,4-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

A racemate of the title compound obtained from8-(3,4-dichlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(132 mg) by the same method as in Examples 65 and 66 was separated byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: ethanol) to obtain the title optically active compoundwith a retention time of 13 minutes and positive optical rotation (24mg) and the title optically active compound with a retention time of 16minutes and negative optical rotation (24 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.16-2.27 (m, 1H), 2.30 (s, 3H), 2.36-2.47 (m,2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H), 4.27-4.43 (m, 2H), 6.92 (brs, 1H),7.05 (d, J=16.4 Hz, 1H), 7.10-7.14 (m, 1H), 7.15-7.27 (m, 5H), 7.57 (d,J=16.4 Hz, 1H), 7.70 (brs, 1H).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.16-2.27 (m, 1H), 2.30 (s, 3H), 2.36-2.47 (m,2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H), 4.27-4.43 (m, 2H), 6.92 (brs, 1H),7.05 (d, J=16.4 Hz, 1H), 7.10-7.14 (m, 1H), 7.15-7.27 (m, 5H), 7.57 (d,J=16.4 Hz, 1H), 7.70 (brs, 1H).

Examples 77, 78, 79 and 80 Synthesis of(−)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile,(+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile,(−)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

8-(3,5-Difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile(80 mg) was obtained from8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(160 mg) by the same method as in Examples 65 and 66. At the same time,8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olgenerated in the reaction step in the middle (80 mg) was isolated.

The resulting8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile(80 mg) was optically resolved by CHIRALPAK™ ADH manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase: 80% ethanol-hexane,flow rate: 10 mL/min) to obtain the title optically active compound witha retention time of 15 minutes and positive optical rotation((+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile,29.6 mg) and the title optically active compound with a retention timeof 18 minutes and negative optical rotation((−)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile,35.1 mg).

The property values of the title optically active compound with aretention time of 18 minutes and negative optical rotation are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 2.16-2.32 (m, 1H), 2.30 (s, 3H), 2.34-2.50 (m,2H), 2.66-2.78 (m, 1H), 3.88 (s, 3H), 4.26-4.44 (m, 2H), 6.84-6.96 (m,4H), 7.06 (d, J=16 Hz, 1H), 7.16-7.22 (m, 2H), 7.24 (d, J=8.4 Hz, 1H),7.59 (d, J=16 Hz, 1H), 7.71 (d, J=0.80 Hz, 1H).

ESI-MS; m/z 473 [M⁺+H].

The property values of the title optically active compound with aretention time of 15 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

8-(3,5-Difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olobtained in the same manner (80 mg) was optically resolved by CHIRALPAK™ADH manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: 50% ethanol-hexane, flow rate: 10 mL/min) to obtain the titleoptically active compound with a retention time of 20 minutes andpositive optical rotation((+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,11.3 mg) and the title optically active compound with a retention timeof 22 minutes and negative optical rotation((−)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,11.6 mg). The property values of the title optically active compoundwith a retention time of 22 minutes and negative optical rotation are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.20 (m, 2H), 2.28 (s, 3H), 2.26-2.40 (m,1H), 2.40-2.56 (m, 1H), 3.77 (s, 3H), 4.18-4.36 (m, 2H), 6.70-6.78 (m,1H), 6.80-6.90 (m, 2H), 6.90-7.05 (m, 4H), 7.11 (d, J=8.0 Hz, 1H), 7.40(d, J=16 Hz, 1H), 7.73 (s, 1H).

ESI-MS; m/z 464 [M⁺+H].

The property values of the title optically active compound with aretention time of 20 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

The following compounds were obtained by the same method as in Examples65 and 66 (Table 3).

TABLE 3

Example E₁ E2 DATA: MS m/z Note 81

CN M⁺ + H: 505 (ESI) Optically active compound (separation conditionsIA: retention time 27 min, optical rotation (−)) 82

CN M⁺ + H: 505 (ESI) Optically active compound (separation conditionsIA: retention time 28 min, optical rotation (+)) 83

CN M⁺ + H: 455 (ESI) Optically active compound (separation conditionsAD-H:ethanol: retention time 15 min, optical rotation (+)) 84

CN M⁺ + H: 455 (ESI) Optically active compound (separation conditionsAD-H:ethanol: retention time 18 min, optical rotation (−)) 85

CN M⁺ + H: 473 (ESI) Optically active compound (separation conditionsIA:80% ethanol-hexane: retention time 15 min, optical rotation (+)) 86

CN M⁺ + H: 473 (ESI) Optically active compound (separation conditionsIA:80% ethanol-hexane: retention time 20 min, optical rotation (−)) 87

CN M⁺ + H: 491 (ESI) Optically active compound (separation conditionsIA:70% ethanol-hexane: retention time 28 min, optical rotation (+)) 88

CN M⁺ + H: 491 (ESI) Optically active compound (separation conditionsIA:70% ethanol-hexane: retention time 33 min, optical rotation (−)) 89

CN M⁺ + H: 489 (ESI) Optically active compound (separation conditionsAD-H:ethanol: retention time 17 min, optical rotation (−)) 90

CN M⁺ + H: 489 (ESI) Optically active compound (separation conditionsAD-H:ethanol: retention time 37 min, optical rotation (+))

Examples 91 and 92 Synthesis of(−)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-(2,4,6-trifluorophenyl)piperidin-1-yl]acrylamide

BOPCl (221 mg) was added to a suspension of(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylicacid (CAS No. 870838-71-4, 240 mg),1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one (106 g) and IPEA (0.45mL) in DMF (5 mL), and the reaction solution was stirred at roomtemperature for 16 hours. Saturated sodium bicarbonate water and ethylacetate were added to the reaction mixture and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 110mg of the title compound. The property value of the compound is asfollows.

ESI-MS; m/z 503 [M⁺+H].

Synthesis of(−)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-(2,4,6-trifluorophenyl)piperidin-1-yl]acrylamide(110 mg) in phosphorus oxychloride (2 mL) was heated under reflux forthree hours. The reaction mixture was left to cool to room temperatureand then concentrated under reduced pressure. Acetic acid (3 mL) andammonium acetate (506 mg) were added to the residue, and the reactionsolution was stirred at 150° C. for two hours. The reaction mixture wasleft to cool to room temperature and then concentrated under reducedpressure. Saturated aqueous sodium bicarbonate and ethyl acetate wereadded to the residue, and the organic layer was separated. The resultingorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (carrier: Chromatorex NH; elution solvent: heptane:ethylacetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) to obtain 42 mg ofa racemate of the title compound. The resulting racemate (22 mg) wasseparated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=1:1) to obtain the titleoptically active compound with a retention time of 10 minutes andnegative optical rotation (3.8 mg) and the title optically activecompound with a retention time of 13 minutes and positive opticalrotation (4.4 mg).

The property values of the title optically active compound with aretention time of 10 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.24 (m, 3H), 2.29 (s, 3H), 2.30-2.39 (m,1H), 3.85 (s, 3H), 4.21-4.30 (m, 1H), 4.37-4.45 (m, 1H), 4.52-4.59 (m,1H), 6.65 (d, J=38.8 Hz, 1H), 6.70 (t, J=8.8 Hz, 2H), 6.92 (brs, 1H),7.21 (d, J=8.0 Hz, 1H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (brs, 1H),7.72 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.24 (m, 3H), 2.29 (s, 3H), 2.30-2.39 (m,1H), 3.85 (s, 3H), 4.21-4.30 (m, 1H), 4.37-4.45 (m, 1H), 4.52-4.59 (m,1H), 6.65 (d, J=38.8 Hz, 1H), 6.70 (t, J=8.8 Hz, 2H), 6.92 (brs, 1H),7.21 (d, J=8.0 Hz, 1H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (brs, 1H),7.72 (d, J=1.2 Hz, 1H).

Examples 93 and 94 Synthesis of(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(−)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazidehydrochloride

A solution of 4 N hydrochloric acid in ethyl acetate (2 mL) was added toa solution of tert-butylN′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(300 mg) in ethyl acetate (2 mL), and the reaction solution was stirredat room temperature for one hour. The reaction solution was concentratedunder reduced pressure to obtain 250 mg of the title compound. Theproperty value of the compound is as follows.

ESI-MS; m/z 281 [M⁺+H].

Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acidN′-{(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide

IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution of5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride(83 mg) and(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylicacid (CAS No. 870838-71-4, 72 mg) in methylene chloride (5 mL), and thereaction solution was stirred at room temperature for 13 hours. Ethylacetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane:ethylacetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) to obtain 84 mg ofthe title compound. The property value of the compound is as follows.

ESI-MS; m/z 539 [M⁺+H].

Synthesis of2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole

A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acidN′-{(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide(84 mg) in phosphorus oxychloride (1 mL) was stirred at 120° C. for 7.5hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure to obtain 81 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 521 [M⁺+H].

Synthesis of2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole(81 mg) and ammonium acetate (358 mg) in acetic acid (2 mL) was stirredat 150° C. for three hours. The reaction solution was left to cool toroom temperature. Then, ethyl acetate and saturated sodium bicarbonatewater were added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (carrier:Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethylacetate) to obtain 98 mg of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.99-2.08 (m, 1H), 2.09-2.28 (m, 2H), 2.31 (s,3H), 2.35-2.44 (m, 1H), 3.87 (s, 3H), 4.28 (t, J=7.2 Hz, 1H), 4.34 (t,J=5.2 Hz, 2H), 6.74 (d, J=38.4 Hz, 1H), 6.82 (dd, J=8.0, 6.4 Hz, 2H),6.94 (brs, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.4, 1.6 Hz, 1H),7.36 (brs, 1H), 7.73 (d, J=0.8 Hz, 1H).

Synthesis of(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(−)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

Sodium hydride (containing 40% of mineral oil, 16.2 mg) was added to asolution of2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(98 mg) in DMF (2 mL), and the reaction solution was stirred at roomtemperature for 40 minutes. Ethyl acetate and a saturated sodiumthiosulfate solution were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was washed withsaturated sodium bicarbonate water, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue wasseparated by CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title opticallyactive compound with a retention time of 9 minutes and positive opticalrotation (22 mg) and the title optically active compound with aretention time of 11 minutes and negative optical rotation (23 mg).

The property values of(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.16 (m, 2H), 2.28 (s, 3H), 2.31-2.39 (m,1H), 2.46-2.58 (m, 1H), 3.77 (s, 3H), 4.23-4.31 (m, 1H), 4.36-4.43 (m,1H), 6.60 (d, J=37.6 Hz, 1H), 6.89 (brs, 1H), 6.98 (dd, J=8.4, 1.6 Hz,1H), 7.06 (dd, J=8.4, 6.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.16 (brs,1H), 7.72 (d, J=1.2 Hz, 1H).

The property values of(−)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-olare as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.16 (m, 2H), 2.28 (s, 3H), 2.31-2.39 (m,1H), 2.46-2.58 (m, 1H), 3.77 (s, 3H), 4.23-4.31 (m, 1H), 4.36-4.43 (m,1H), 6.60 (d, J=37.6 Hz, 1H), 6.89 (brs, 1H), 6.98 (dd, J=8.4, 1.6 Hz,1H), 7.06 (dd, J=8.4, 6.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.16 (brs,1H), 7.72 (d, J=1.2 Hz, 1H).

Examples 95 and 96 Synthesis of(+)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(−)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

Synthesis of(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylicacid

Lithium hydroxide monohydrate (240 mg) was added to a mixed solution of2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (CAS No.870851-52-8, 1.03 g) and triethyl phosphonoacetate (1.09 g) in THF (4mL)-ethanol (1 mL), and the reaction solution was stirred at roomtemperature for five hours. A 2 N sodium hydroxide solution (4 mL) wasadded to the reaction solution, and the reaction solution was stirredfor 17 hours. 2 N aqueous hydrochloric acid (4 mL) was added to thereaction solution, and the reaction solution was stirred at roomtemperature for 30 minutes. The precipitated solid was collected byfiltration and washed with water and ether. The resulting solid wasair-dried to obtain 1.03 g of the title compound. The property value ofthe compound is as follows.

ESI-MS; m/z 277 [M⁺+H].

Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acidN′-{(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide

IPEA (0.31 mL) and BOPCl (119 mg) were added to a solution of5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride(114 mg) and(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylicacid (99 mg) in methylene chloride (5 mL), and the reaction solution wasstirred at room temperature for one hour. Ethyl acetate and a saturatedammonium chloride solution were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain 200 mg of the title compound. The property value of the compoundis as follows.

ESI-MS; m/z 539 [M⁺+H].

Synthesis of2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole

A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acidN′-{(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide(200 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for 5.5hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. Ethyl acetate and saturatedsodium bicarbonate water were added to the residue, and the organiclayer was separated. The resulting organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain 180 mg of the title compound. The property value of the compoundis as follows.

ESI-MS; m/z 521 [M⁺+H].

Synthesis of(+)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-oland(−)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

A solution of2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole(180 mg) and ammonium acetate (533 mg) in acetic acid (2 mL) was stirredat 150° C. for 24 hours. The reaction solution was left to cool to roomtemperature. Then, ethyl acetate and saturated sodium bicarbonate waterwere added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane:ethyl acetate=1:1→ethyl acetate→ethylacetate:methanol=4:1) to obtain a racemate of the title compound. Sodiumhydride (40% oil suspension, 22.2 mg) was added to a solution of theresulting racemate (134 mg) in DMF (2 mL), and the reaction solution wasstirred at room temperature for one hour. Ethyl acetate and a saturatedsodium thiosulfate solution were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was washed withsaturated sodium bicarbonate water, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue wasseparated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the titleoptically active compound with a retention time of 7 minutes (26 mg) andthe title optically active compound with a retention time of 8 minutes(24 mg).

The property values of the title optically active compound with aretention time of 7 minutes are as follows.

ESI-MS; m/z 500 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.14 (m, 2H), 2.26(s, 3H), 2.28-2.36 (m, 1H), 2.45-2.57 (m, 1H), 3.74 (s, 3H), 4.17-4.25(m, 1H), 4.28-4.37 (m, 1H), 6.83 (brs, 1H), 6.88 (d, J=10.4 Hz, 1H),6.89 (d, J=6.4 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.06 (dd, J=8.8, 6.4Hz, 2H), 7.42 (d, J=16.4 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H).

The property values of the title optically active compound with aretention time of 8 minutes are as follows.

ESI-MS; m/z 500 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.14 (m, 2H), 2.26(s, 3H), 2.28-2.36 (m, 1H), 2.45-2.57 (m, 1H), 3.74 (s, 3H), 4.17-4.25(m, 1H), 4.28-4.37 (m, 1H), 6.83 (brs, 1H), 6.88 (d, J=10.4 Hz, 1H),6.89 (d, J=6.4 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.06 (dd, J=8.8, 6.4Hz, 2H), 7.42 (d, J=16.4 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H).

Examples 97, 98, 99 and 100 Synthesis of(6R,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,(6R,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,(6S,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(6S,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

388 mg of a diastereomer mixture of the title compound was obtained from(E)-N-[3-(4-fluorophenyl)-5-methyl-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide(662 mg) using methyl 4-fluorophenylacetate and1-bromo-3-chloro-2-methylpropane as starting materials by the samemethod as in Examples 20 and 21. The resulting diastereomer mixture (388mg) was separated by CHIRALPAK™ OD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to obtain the title optically active compound with a retentiontime of 10 minutes and negative optical rotation (67 mg), the titleoptically active compound with a retention time of 13 minutes andpositive optical rotation (69 mg), the title optically active compoundwith a retention time of 15 minutes and negative optical rotation (93mg) and the title optically active compound with a retention time of 30minutes and positive optical rotation (92 mg).

The property values of the title optically active compound with aretention time of 10 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.12 (d, J=6.8 Hz, 3H), 2.08-2.11 (m, 2H), 2.30(s, 3H), 2.31-2.37 (m, 1H), 3.76 (dd, J=12.8 Hz, 9.6 Hz, 1H), 3.87 (s,3H), 4.37 (dd, J=12.8 Hz, 5.2 Hz, 1H), 4.49 (t, J=4.4 Hz, 1H), 6.92 (t,J=0.8 Hz, 1H), 7.00-7.03 (m, 4H), 7.08 (d, J=16.4 Hz, 1H), 7.14-7.17 (m,2H), 7.23 (d, J=8.0 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.6 Hz,1H).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.12 (d, J=6.8 Hz, 3H), 2.08-2.11 (m, 2H), 2.30(s, 3H), 2.31-2.37 (m, 1H), 3.76 (dd, J=12.8 Hz, 9.6 Hz, 1H), 3.87 (s,3H), 4.37 (dd, J=12.8 Hz, 5.2 Hz, 1H), 4.49 (t, J=4.4 Hz, 1H), 6.92 (t,J=0.8 Hz, 1H), 7.00-7.03 (m, 4H), 7.08 (d, J=16.4 Hz, 1H), 7.14-7.17 (m,2H), 7.23 (d, J=8.0 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.6 Hz,1H).

The property values of the title optically active compound with aretention time of 15 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.20 (d, J=6.4 Hz, 3H), 1.66-1.76 (m, 1H), 2.29(s, 3H), 2.30-2.42 (m, 2H), 3.76-3.83 (m, 1H), 3.85 (s, 3H), 4.19 (dd,J=11.6 Hz, 5.6 Hz, 1H), 4.36 (dd, J=11.6 Hz, 5.6 Hz, 1H), 6.91 (t, J=1.2Hz, 1H), 7.02-7.07 (m, 3H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 3H), 7.48(d, J=16.0 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H).

The property values of the title optically active compound with aretention time of 30 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.20 (d, J=6.4 Hz, 3H), 1.66-1.76 (m, 1H), 2.29(s, 3H), 2.30-2.42 (m, 2H), 3.76-3.83 (m, 1H), 3.85 (s, 3H), 4.19 (dd,J=11.6 Hz, 5.6 Hz, 1H), 4.36 (dd, J=11.6 Hz, 5.6 Hz, 1H), 6.91 (t, J=1.2Hz, 1H), 7.02-7.07 (m, 3H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 3H), 7.48(d, J=16.0 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H).

Examples 101 and 102 Synthesis of(7S,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(7R,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 3-(tert-butyldiphenylsilanyloxy)-1-methylpropyltoluene-4-sulfonate

Triethylamine (4.64 mL), p-toluenesulfonyl chloride (4.66 g) and DMAP(271 mg) were added to a solution of4-(tert-butyldiphenylsilanyloxy)butan-2-ol (7.3 g; CAS #114079-44-6) in1,2-dichloroethane (80 mL) at 0° C., and the reaction solution wasstirred at 60° C. for three hours. The reaction solution was left tocool to room temperature and then concentrated under reduced pressure.Ethyl acetate and brine were added to the residue, and the organic layerwas separated. The resulting organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 6.4 g of the title compound. Theproperty value of the compound is as follows.

ESI-MS; m/z 505 [M⁺+Na].

Synthesis of5-(tert-butyldiphenylsilanyloxy-2-(4-fluorophenyl)-3-methylpentanoicacid

n-Butyl lithium (4.89 mL; 2.66 M solution in hexane) was added dropwiseto a solution of 4-fluorophenylacetic acid (1 g) in THF (30 mL) at −78°C., and the reaction solution was stirred for 20 minutes. The reactionsolution was heated to 0° C. and stirred for 30 minutes. Then, asolution of 3-(tert-butyldiphenylsilanyloxy)-1-methylpropyltoluene-4-sulfonate (3.2 g) in THF (10 mL) was added dropwise to thereaction solution. The reaction solution was heated to room temperatureand stirred at the same temperature for 12 hours. Then, 1 N hydrochloricacid and ethyl acetate were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was washed withbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain986 mg of the title compound. The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 0.64 (d, J=6.8 Hz, 3H), 1.04 (s, 9H), 1.31-1.43(m, 1H), 1.79-1.86 (m, 1H), 2.29-2.45 (m, 1H), 3.31 (d, J=10.0 Hz, 1H),3.67-3.78 (m, 2H), 6.98 (t, J=8.8 Hz, 2H), 7.21-7.28 (m, 3H), 7.32-7.42(m, 5H), 7.65 (d, J=7.6 Hz, 4H).

Synthesis of tert-butylN′-[5-(tert-butyldiphenylsilanyloxy)-2-(4-fluorophenyl)-3-methylpentanoyl]hydrazinecarboxylate

BOPCl (860 mg) and IPEA (0.552 mL) were added to a solution of5-(tert-butyldiphenylsilanyloxy-2-(4-fluorophenyl)-3-methylpentanoicacid (980 mg) and tert-butyl carbazate (558 mg) in methylene chloride(15 mL) at 0° C. The reaction solution was stirred at room temperaturefor 15 hours. Then, ethyl acetate and a saturated ammonium chloridesolution were added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 1.04 g of thetitle compound. The property value of the compound is as follows.

ESI-MS; m/z 601 [M⁺+Na].

Synthesis of tert-butylN′-[2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate

TBAF (2.7 mL; 1 M solution in THF) was added to a solution of tert-butylN′-[5-(tert-butyldiphenylsilanyloxy)-2-(4-fluorophenyl)-3-methylpentanoyl]hydrazinecarboxylate(1.04 g) in THF (20 mL). The reaction solution was stirred at roomtemperature for 1 hours. Then, ethyl acetate and a saturated ammoniumchloride solution were added to the reaction solution, and the organiclayer was separated. The resulting organic layer was washed with brine,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain525 mg of the title compound. The property value of the compound is asfollows.

ESI-MS; m/z 363 [M⁺+Na].

Synthesis of5-(N′-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3-methyl-5-oxo-1-pentyltoluene-4-sulfonate

p-Toluenesulfonyl chloride (321 mg) was added to a solution oftert-butylN′-[2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate(520 mg) in pyridine (6 mL). The reaction solution was stirred at roomtemperature for 12 hours and then concentrated under reduced pressure.Ethyl acetate and brine were added to the residue, and the organic layerwas separated. The resulting organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 335 mg of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 517 [M⁺+Na].

Synthesis of tert-butylN′-[5-chloro-2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate

Lithium chloride (283 mg) was added to a solution of5-(N′-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3-methyl-5-oxo-1-pentyltoluene-4-sulfonate (330 mg) in DMF (5 mL). The reaction solution wasstirred at 80° C. for three hours and then left to cool to roomtemperature. Water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was washed with brine, and then dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 170 mg of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 381 [M⁺+Na].

Synthesis of(7S,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(7R,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A solution of 4 N hydrochloric acid in ethyl acetate (3 mL) was added totert-butylN′-[5-chloro-2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate(170 mg). The reaction solution was stirred at room temperature for twohours and then concentrated under reduced pressure. Subsequently,triethylamine (0.292 mL) was added to a solution of the residue inethanol (3 mL). A mixed solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (150 mg) and triethylamine (0.292 mL) in ethanol (3 mL)was added dropwise to the solution, and the reaction solution wasstirred at 80° C. for 12 hours. The reaction solution was left to coolto room temperature and then concentrated under reduced pressure.Saturated sodium bicarbonate water and ethyl acetate were added to theresulting residue, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent: ethylacetate-methanol system) to obtain a racemate of the title compound. Theresulting racemate was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1)to obtain the title optically active compound with a retention time of25 minutes (20.7 mg, >99% ee) and the title optically active compoundwith a retention time of 36 minutes (22.4 mg, >99% ee).

The property values of the title compound with a retention time of 25minutes are as follows.

ESI-MS; m/z 444 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.06 (d, J=6.4 Hz, 3H),1.88-2.00 (m, 1H), 2.11-2.25 (m, 2H), 2.29 (s, 3H), 3.72 (d, J=9.2 Hz,1H), 3.84 (s, 3H), 4.26-4.37 (m, 2H), 6.90 (s, 1H), 7.00-7.12 (m, 7H),7.19 (d, J=8.0 Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.69 (s, 1H).

The property values of the title compound with a retention time of 36minutes are as follows.

ESI-MS; m/z 444 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.06 (d, J=6.4 Hz, 3H),1.88-2.00 (m, 1H), 2.11-2.25 (m, 2H), 2.29 (s, 3H), 3.72 (d, J=9.2 Hz,1H), 3.84 (s, 3H), 4.26-4.37 (m, 2H), 6.90 (s, 1H), 7.00-7.12 (m, 7H),7.19 (d, J=8.0 Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.69 (s, 1H).

Examples 103 and 104 Synthesis of(7S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-oland(7R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

Synthesis of benzyl (3,4,5-trifluorophenyl)acetate

Triethylamine (0.808 mL) and benzyl chloroformate (0.752 mL) weresequentially added dropwise to a solution of 3,4,5-trifluorophenylaceticacid (1 g) in methylene chloride (15 mL) at 0° C., and the reactionsolution was stirred at 0° C. for five minutes. DMAP (64.4 mg) was addedto the reaction solution which was then stirred at 0° C. for 30 minutes.Ethyl acetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 1.43 g of the title compound.The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 3.59 (s, 2H), 5.14 (s, 2H), 6.90 (dd, J=8.0, 6.4Hz, 2H), 7.29-7.38 (m, 5H), 3.83 (s, 3H), 3.89 (s, 3H), 6.44 (s, 1H),6.95 (brs, 1H), 7.04 (d, J=1.6 Hz, 1H), 7.07 (dd, J=8.0, 1.6 Hz, 1H),7.20 (t, J=8.8 Hz, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H),7.83 (s, 1H), 8.09 (dd, J=8.8, 5.2 Hz, 2H).

Synthesis of benzyl(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoateand benzyl(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate

n-Butyl lithium (1.82 mL; 2.66 M solution in hexane) was added dropwiseto a solution of diisopropylamine (0.735 mL) in THF (6 mL) at 0° C. Thereaction solution was stirred at 0° C. for 20 minutes and then cooled to−78° C. Benzyl (3,4,5-trifluorophenyl)acetate (1.13 g) in THF (18 mL)was added dropwise to the reaction solution, and the reaction solutionwas stirred at −78° C. for 15 minutes. Thereafter,3-(tert-butyldiphenylsiloxy)propanol (CAS No. 112897-03-7, 1.26 g) inTHF (6 mL) was added dropwise to the reaction solution, and the reactionsolution was stirred at −78° C. for 30 minutes. A saturated ammoniumchloride solution was added to the reaction solution, and the reactionsolution was returned to room temperature. Ethyl acetate was added andthe organic layer was separated. The resulting organic layer was washedwith brine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain840 mg of benzyl(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoateand 765 mg of benzyl(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate.

The property values of benzyl(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoateare as follows.

ESI-MS; m/z 615 [M⁺+Na]. ¹H-NMR (CDCl₃) δ (ppm): 1.03 (s, 9H), 1.57-1.62(m, 2H), 3.49 (d, J=2.4 Hz, 1H), 3.57 (d, J=6.8 Hz, 1H), 3.77-3.85 (m,2H), 4.46 (m, 1H), 5.07 (d, J=12.4 Hz, 1H), 5.14 (d, J=12.4 Hz, 1H),7.02 (dd, J=8.8, 6.4 Hz, 2H), 7.20-7.45 (m, 11H), 7.62 (d, J=8.0 Hz,4H).

The property values of benzyl(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoateare as follows.

ESI-MS; m/z 615 [M⁺+Na]. ¹H-NMR (CDCl₃) δ (ppm): 1.03 (s, 9H), 1.45-1.51(m, 2H), 3.54 (d, J=4.0 Hz, 1H), 3.57 (d, J=9.2 Hz, 1H), 3.73-3.81 (m,2H), 4.38 (m, 1H), 5.13 (d, J=12.4 Hz, 1H), 5.19 (d, J=12.4 Hz, 1H),6.91 (dd, J=8.8, 6.4 Hz, 2H), 7.24-7.44 (m, 11H), 7.57-7.62 (m, 4H).

Synthesis of benzyl(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoate

IPEA (0.742 mL) and chloromethyl methyl ether (0.324 mL) were added to asolution of benzyl(2S,3R)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate(840 mg) in 1,2-dichloroethane (20 mL) at 0° C. The reaction solutionwas stirred at 60° C. for 4 hours and then left to cool to roomtemperature and concentrated under reduced pressure. Ethyl acetate and asaturated ammonium chloride solution were added to the residue, and theorganic layer was separated. The resulting organic layer was washed withbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain875 mg of the title compound. The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.03 (s, 9H), 1.55-1.64 (m, 1H), 1.70-1.82 (m,1H), 3.11 (s, 3H), 3.60-3.73 (m, 2H), 3.74 (d, J=6.0 Hz, 1H), 4.38-4.41(m, 1H), 4.39 (d, J=6.4 Hz, 1H), 4.51 (d, J=6.4 Hz, 1H), 5.12 (s, 2H),6.95 (dd, J=8.8, 6.8 Hz, 2H), 7.25-7.43 (m, 11H), 7.61 (d, J=8.0 Hz,4H).

Synthesis of tert-butylN′-[(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

Palladium-carbon (258 mg; 10 wt %) was added to a solution of benzyl(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoate(770 mg) in methanol (10 mL). The reaction solution was stirred in ahydrogen atmosphere for two hours and then filtered through celite, andthe filtrate was concentrated under reduced pressure. Subsequently,BOPCl (493 mg) and IPEA (0.316 mL) were added to a solution of theresidue of tert-butyl carbazate (320 mg) in methylene chloride (20 mL)at 0° C. The reaction solution was stirred at room temperature for 15hours. Then, ethyl acetate and a saturated ammonium chloride solutionwere added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 603 mg of thetitle compound. The property value of the compound is as follows.

ESI-MS; m/z 683 [M⁺+Na].

Synthesis of tert-butylN′-[(2S*,3R*)-5-hydroxy-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

TBAF (1.36 mL; 1 M solution in THF) was added to a solution oftert-butylN′-[(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(600 mg) in THF (10 mL). The reaction solution was stirred at roomtemperature for one hour. Then, ethyl acetate and a saturated ammoniumchloride solution were added to the reaction solution, and the organiclayer was separated. The resulting organic layer was washed with brine,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain383 mg of the title compound. The property value of the compound is asfollows.

ESI-MS; m/z 445 [M⁺+Na].

Synthesis of tert-butylN′-[(2S*,3R*)-5-chloro-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

Triethylamine (0.209 mL) and methanesulfonyl chloride (58 uL) were addedto a solution of tert-butylN′-[(2S*,3R*)-5-hydroxy-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(264 mg) in methylene chloride (10 mL) at 0° C. The reaction solutionwas stirred at 0° C. for 30 minutes. Then, ethyl acetate and saturatedsodium bicarbonate water were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was washed withbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. Subsequently, lithium chloride (265 mg) wasadded to a solution of the residue in DMF (5 mL), and the reactionsolution was stirred at 80° C. for three hours. The reaction solutionwas left to cool to room temperature. Then, water and ethyl acetate wereadded to the reaction solution, and the organic layer was separated. Theresulting organic layer was washed with brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system) to obtain 87.5 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 463 [M⁺+Na].

Synthesis of(7S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-oland(7R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

A solution of 4 N hydrochloric acid in ethyl acetate (2 mL) was added totert-butylN′-[(2S*,3R*)-5-chloro-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(100 mg). The reaction solution was stirred at room temperature for twohours and then concentrated under reduced pressure. Subsequently,triethylamine (0.156 mL) was added to a solution of the residue inethanol (2.5 mL). A mixed solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (80 mg) and triethylamine (0.156 mL) in ethanol (2.5 mL)was added dropwise to the solution, and the reaction solution wasstirred at 80° C. for 12 hours. The reaction solution was left to coolto room temperature and then concentrated under reduced pressure.Saturated sodium bicarbonate water and ethyl acetate were added to theresulting residue, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain a racemate of the titlecompound. The resulting racemate was separated by CHIRALCEL™ OD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=8:2) to obtain the title optically active compoundwith a retention time of 11 minutes (8.2 mg, >99% ee) and the titleoptically active compound with a retention time of 17 minutes (7.4mg, >99% ee).

The property values of the title compound with a retention time of 11minutes are as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.20-2.35 (m, 2H), 2.27(s, 3H), 3.84 (s, 3H), 4.26-4.34 (m, 3H), 4.39-4.45 (m, 1H), 6.77 (dd,J=8.0, 6.8 Hz, 2H), 6.90 (d, J=1.2 Hz, 1H), 7.01 (d, J=16.4 Hz, 1H),7.07 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.45 (d,J=16.4 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H).

The property values of the title compound with a retention time of 17minutes corresponded to the property values of the title compound with aretention time of 11 minutes.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.20-2.35 (m, 2H), 2.27(s, 3H), 3.84 (s, 3H), 4.26-4.34 (m, 3H), 4.39-4.45 (m, 1H), 6.77 (dd,J=8.0, 6.8 Hz, 2H), 6.86 (d, J=7.2 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 7.01(d, J=16.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.20(d, J=8.4 Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H).

Examples 105 and 106 Synthesis of(7R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-oland(7S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

(1) Synthesis of(7R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-oland(7S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-ol

A racemate of the title compound (55.1 mg) was obtained from benzyl(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate(1.01 g) by the same method as in Examples 103 and 104. The resultingracemate was separated by CHIRALPAK™ AD-H manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtainthe title optically active compound with a retention time of 6 minutes(11.0 mg, >99% ee) and the title optically active compound with aretention time of 11 minutes (8.6 mg, >99% ee).

The property values of the title compound with a retention time of 6minutes are as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.20-2.40 (m, 2H), 2.28(s, 3H), 3.85 (s, 3H), 4.20-4.34 (m, 3H), 4.40-4.47 (m, 1H), 6.79 (dd,J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 7.01 (d, J=16.0 Hz, 1H), 7.10 (d,J=8.8 Hz, 1H), 7.11 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.46 (d, J=16.0 Hz,1H), 7.59 (s, 1H).

The property values of the title compound with a retention time of 11minutes corresponded to the property values of the title compound with aretention time of 6 minutes.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.20-2.40 (m, 2H), 2.28(s, 3H), 3.85 (s, 3H), 4.20-4.34 (m, 3H), 4.40-4.47 (m, 1H), 6.79 (dd,J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 7.01 (d, J=16.0 Hz, 1H), 7.10 (d,J=8.8 Hz, 1H), 7.11 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.46 (d, J=16.0 Hz,1H), 7.59 (s, 1H).

Examples 107, 108, 109 and 110 Synthesis of(6R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol,(6S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol,(6S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-oland(6R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol

Synthesis of 2-(3,4,5-trifluorophenyl)-4-pentenoic acid

n-Butyl lithium (7.89 mL; 2.66 M solution in hexane) was added to asolution of 3,4,5-trifluorophenylacetic acid (2 g) in THF (50 mL) at−78° C. The reaction solution was stirred at −78° C. for 20 minutes.Then, the reaction solution was heated to 0° C. and further stirred for30 minutes. Allyl bromide (0.999 mL) was added dropwise to the reactionsolution, and the reaction solution was stirred at room temperature forthree hours. A 1 N sodium hydroxide solution and diethyl ether wereadded to the reaction solution, and the aqueous layer was separated. 5 Nhydrochloric acid and ethyl acetate were added to the resulting aqueouslayer, and the organic layer was separated. The resulting organic layerwas washed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 1.45 g of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.44-2.52 (m, 1H), 2.72-2.81 (m, 1H), 3.58 (t,J=7.6 Hz, 1H), 5.03-5.10 (m, 2H), 5.60-5.71 (m, 1H), 6.90 (dd, J=8.4,6.4 Hz, 2H).

Synthesis of tert-butylN′-[2-(3,4,5-trifluorophenyl)penten-4-oyl]hydrazinecarboxylate

BOPCl (2.57 g) and IPEA (1.65 mL) were added to a solution of2-(3,4,5-trifluorophenyl)-4-pentenoic acid (1.45 g) and tert-butylcarbazate (1.94 g) in methylene chloride (30 mL) at 0° C. The reactionsolution was stirred at room temperature for 15 hours. Then, ethylacetate and a saturated ammonium chloride solution were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 1.77 g of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 345 [M⁺+H].

Synthesis of tert-butylN′-[4,5-dihydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

Osmium tetroxide (2.61 mL; 2.5 wt %) was added to a solution oftert-butylN′-[2-(3,4,5-trifluorophenyl)penten-4-oyl]hydrazinecarboxylate (1.77 g)and N-methylmorpholine N-oxide (1.81 g) in acetone (40 mL) and water (40mL). The reaction solution was stirred at room temperature for 4 hours.Then, ethyl acetate and a saturated sodium thiosulfate solution wereadded to the reaction solution, and the organic layer was separated. Theresulting organic layer was washed with 1 N hydrochloric acid and brine,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: ethyl acetate-methanol system) to obtain 1.09 g of thetitle compound. The property value of the compound is as follows.

ESI-MS; m/z 401 [M⁺+Na].

Synthesis of5-(N′-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4-(3,4,5-trifluorophenyl)pentyltoluene-4-sulfonate

p-Toluenesulfonyl chloride (605 mg) was added to a solution oftert-butylN′-[4,5-dihydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(1.09 g) in pyridine (11 mL) at room temperature. The reaction solutionwas stirred at room temperature for 12 hours and then concentrated underreduced pressure. Ethyl acetate was added to the residue, and theorganic layer was washed with brine, dried over anhydrous sodium sulfateand then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (elution solvent: heptane-ethylacetate system) to obtain 1.03 g of the title compound. The propertyvalue of the compound is as follows.

ESI-MS; m/z 555 [M⁺+H].

Synthesis of tert-butylN′-[5-chloro-4-hydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

Lithium chloride (818 mg) was added to a solution of5-(N′-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4-(3,4,5-trifluorophenyl)pentyltoluene-4-sulfonate (1.03 g) in DMF (8 mL). The reaction solution wasstirred at 80° C. for three hours and then left to cool to roomtemperature. Water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was washed with brine, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 734 mg of the title compound. The property value ofthe compound is as follows.

ESI-MS; m/z 419 [M⁺+Na].

Synthesis of tert-butylN′-[4-(tert-butyldiphenylsilanyloxy)-5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate

tert-Butyldiphenylchlorosilane (0.889 mL), imidazole (233 mg) and DMAP(41.9 mg) were added to a solution of tert-butylN′-[5-chloro-4-hydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(680 mg) in DMF (5 mL). The reaction solution was stirred at 60° C. fortwo hours and then left to cool to room temperature. A saturatedammonium chloride solution and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was washed with brine, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 831 mg of the title compound. The property value ofthe compound is as follows.

ESI-MS; m/z 657 [M⁺+Na].

Synthesis of6-(tert-butyldiphenylsilanyloxy)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

TFA (5 mL) was added dropwise to a solution of tert-butylN′-[4-(tert-butyldiphenylsilanyloxy)-5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate(830 mg) in methylene chloride (10 mL) at 0° C. The reaction solutionwas stirred at room temperature for two hours. Then, saturated sodiumbicarbonate water and chloroform were added, and the organic layer wasseparated. The aqueous layer was extracted with chloroform twice. Theresulting organic layers were combined, washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. Subsequently, triethylamine (1.28 mL) was added to a solutionof the residue in ethanol (10 mL). A mixed solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (400 mg) in ethanol (10 mL) and triethylamine (1.28 mL)was added dropwise to the solution, and the reaction solution wasstirred at 80° C. for 12 hours. The reaction solution was left to coolto room temperature and then concentrated under reduced pressure.Saturated sodium bicarbonate water and ethyl acetate were added to theresulting residue, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 510 mg of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 720 [M⁺+H].

Synthesis of(6R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol,(6S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol,(6S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-oland(6R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-ol

TBAF (1.06 mL; 1 M solution in THF) was added to a solution of6-(tert-butyldiphenylsilanyloxy)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(510 mg) in THF (10 mL), and the reaction solution was stirred at roomtemperature for one hour. Saturated sodium bicarbonate water and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: ethyl acetate-methanol system) to obtain adiastereomer mixture of the title compound. The resulting mixture wasseparated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain(6R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-oland(6S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-olas an optically active compound with a retention time of 5.8 minutes(40.6 mg) and an optically active compound with a retention time of 7.1minutes (39.0 mg), respectively.

The property values of the compound with a retention time of 5.8 minutesare as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CD₃OD) δ (ppm): 1.90-2.20 (m, 1H), 2.24(s, 3H), 2.40-2.49 (m, 1H), 3.91 (s, 3H), 4.25 (d, J=13.2 Hz, 1H),4.41-4.53 (m, 3H), 7.06 (d, J=1.6 Hz, 1H), 7.08 (d, J=16.0 Hz, 1H), 7.14(dd, J=8.8, 6.0 Hz, 1H), 7.23 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 7.79 (s, 1H).

The property values of the compound with a retention time of 7.1 minutesare as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CD₃OD) δ (ppm): 1.90-2.20 (m, 1H), 2.24(s, 3H), 2.40-2.49 (m, 1H), 3.91 (s, 3H), 4.25 (d, J=13.2 Hz, 1H),4.41-4.53 (m, 3H), 7.06 (d, J=1.6 Hz, 1H), 7.08 (d, J=16.0 Hz, 1H), 7.14(dd, J=8.8, 6.0 Hz, 1H), 7.23 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 7.79 (s, 1H).

The remaining diastereomers were separated by CHIRALPAK™ AD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain(6S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-oland(6R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-olas an optically active compound with a retention time of 6.2 minutes(10.2 mg) and an optically active compound with a retention time of 8.2minutes (7.4 mg), respectively.

The property values of the compound with a retention time of 6.2 minutesare as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CD₃OD) δ (ppm): 2.06-2.15 (m, 1H), 2.23(s, 3H), 2.49-2.55 (m, 1H), 3.90 (s, 3H), 4.06 (dd, J=12.0, 8.0 Hz, 1H),4.35-4.48 (m, 3H), 7.03-7.12 (m, 2H), 7.15 (dd, J=8.8, 6.4 Hz, 2H), 7.22(dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H),7.46 (d, J=16.4 Hz, 1H), 7.79 (s, 1H).

The property values of the compound with a retention time of 8.2 minutesare as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CD₃OD) δ (ppm): 2.06-2.15 (m, 1H), 2.23(s, 3H), 2.49-2.55 (m, 1H), 3.90 (s, 3H), 4.06 (dd, J=12.0, 8.0 Hz, 1H),4.35-4.48 (m, 3H), 7.03-7.12 (m, 2H), 7.15 (dd, J=8.8, 6.4 Hz, 2H), 7.22(dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H),7.46 (d, J=16.4 Hz, 1H), 7.79 (s, 1H).

Examples 111 and 112 Synthesis of (−) and(+)-8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butylN′-(5-chloro-2-cyclopropyl-pentanoyl)-hydrazinecarboxylate

n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was added dropwiseto a solution of diisopropylamine (1.5 ml) in THF (15 ml) at −30° C.,and the reaction solution was stirred at the same temperature for 15minutes. The reaction solution was cooled to −78° C. Then, a solution ofcyclopropylacetic acid (CAS No. 5239-82-7, 500 mg) in THF (3 ml) wasadded dropwise and the reaction solution was further stirred at roomtemperature for three hours. The reaction solution was cooled to 0° C.,and then 1-bromo-3-chloropropane (CAS No. 109-70-6, 0.55 ml) was addeddropwise. The reaction solution was stirred at the same temperature for10 minutes and at room temperature for further one hour. Ice water anddiethyl ether were added to the reaction solution, and the aqueous layerwas separated. Then, 5 N hydrochloric acid (3 ml) and ethyl acetate wereadded to the aqueous layer, and the organic layer was separated. Theresulting ethyl acetate layer was washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reduced pressureto obtain crude 5-chloro-2-cyclopropyl-valeric acid (550 mg).

IPEA (1.6 ml) and BOPCl (1.2 g) were added to a solution of the crude5-chloro-2-cyclopropyl-valeric acid (550 mg) and tert-butyl carbazate(CAS No. 870-46-2, 555 mg) in methylene chloride (5 ml), and thereaction solution was stirred at room temperature for three hours. Ethylacetate and water were added to the reaction solution, and the organiclayer was separated. The organic layer was sequentially washed with 1 Nhydrochloric acid, water, a saturated sodium bicarbonate solution andbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (elution solvent: heptane-ethyl acetate system) toobtain 210 mg of the title compound. The property value of the compoundis as follows.

ESI-MS; m/z 313 [M⁺+Na]. ¹H-NMR (CDCl₃) δ (ppm): 0.20-0.31 (m, 2H),0.57-0.70 (m, 2H), 0.90-1.00 (m, 1H), 1.43-1.55 (m, 1H), 1.48 (s, 9H),1.81-1.97 (m, 4H), 3.49-3.60 (m, 2H), 6.48 (brs, 1H), 7.38 (brs, 1H).

Synthesis of 5-chloro-2-cyclopropyl-valeric acid hydrazide

Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butylN′-(5-chloro-2-cyclopropyl-pentanoyl)-hydrazinecarboxylate (208 mg) inmethylene chloride (1 ml) under ice-cooling, and then the reactionsolution was stirred at room temperature for two hours. A saturatedsodium bicarbonate solution and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The organic layer wassequentially washed with a saturated sodium bicarbonate solution andbrine. The combined aqueous layers were reextracted with ethyl acetate(twice). The combined organic layers were dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure to obtain 127 mg ofthe title compound. The property values of the compound are as follows.

ESI-MS; m/z 191 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 0.16-0.24 (m, 2H),0.52-0.68 (m, 2H), 0.86-0.95 (m, 1H), 1.31-1.37 (m, 1H), 1.78-2.00 (m,4H), 3.48-3.60 (m, 2H), 3.96 (brs, 2H), 6.88 (brs, 1H).

Synthesis of (−) and(+)-8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of 5-chloro-2-cyclopropyl-valeric acid hydrazide (125 mg) inethanol (1.5 mL) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (259 mg) and TEA (0.46 ml) in ethanol (3 ml), and thereaction solution was stirred at 70° C. for 22 hours. The reactionsolution was left to cool to room temperature. Then, ethyl acetate andwater were added to the reaction solution, and the organic layer wasseparated. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetatesystem) and again purified by silica gel column chromatography (elutionsolvent: ethyl acetate-methanol system) to obtain 43 mg of racemic8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.Then, the racemate was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: 20% ethanol-hexane)to obtain the title optically active compound with a retention time of28 minutes and negative optical rotation (16.4 mg; 100% ee) and thetitle optically active compound with a retention time of 49 minutes andpositive optical rotation (16.3 mg; 99% ee).

The property values of the title optically active compound with aretention time of 28 minutes are as follows.

ESI-MS; m/z 376 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 0.31-0.39 (m, 1H),0.52-0.65 (m, 2H), 0.73-0.81 (m, 1H), 0.99-1.09 (m, 1H), 1.83-1.93 (m,1H), 1.97-2.17 (m, 2H), 2.21-2.32 (m, 1H), 2.30 (s, 3H), 2.33-2.40 (m,1H), 3.88 (s, 3H), 4.16 (t, J=6.0 Hz, 2H), 6.91 (d, J=0.8 Hz, 1H), 7.08(d, J=16.4 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz,1H), 7.22 (d, J=8.0 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.69 (d, J=0.8 Hz,1H).

The property values of the title optically active compound with aretention time of 49 minutes are as follows.

ESI-MS; m/z 376 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 0.31-0.39 (m, 1H),0.52-0.65 (m, 2H), 0.73-0.81 (m, 1H), 0.99-1.09 (m, 1H), 1.83-1.93 (m,1H), 1.97-2.17 (m, 2H), 2.21-2.32 (m, 1H), 2.30 (s, 3H), 2.33-2.40 (m,1H), 3.88 (s, 3H), 4.16 (t, J=6.0 Hz, 2H), 6.91 (d, J=0.8 Hz, 1H), 7.08(d, J=16.4 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz,1H), 7.22 (d, J=8.0 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.69 (d, J=0.8 Hz,1H).

Examples 113 and 114 Synthesis of (+) and(−)-8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of methyl 5-chloro-2-cyclohexyl-valerate

n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was added dropwiseto a solution of diisopropylamine (1.55 ml) in THF (15 ml) underice-cooling, and the reaction solution was stirred at the sametemperature for 10 minutes. The reaction solution was cooled to −78° C.Then, a solution of methyl cyclohexylacetate (CAS No. 14352-61-5, 500mg) in THF (3 ml) was added dropwise and the reaction solution wasstirred at the same temperature for 30 minutes. Then,1-chloro-3-iodopropane (CAS No. 6940-76-7, 1.1 ml) was added dropwise tothe reaction solution. The reaction solution was stirred at the sametemperature for 20 minutes and then gradually heated to roomtemperature. Water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The organic layer wassequentially washed with 1 N hydrochloric acid, water, a saturatedsodium bicarbonate solution and brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (elutionsolvent: hexane-diethyl ether system) to obtain 1.00 g of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 233 [M⁺+H].

Synthesis of tert-butylN′-(5-chloro-2-cyclohexyl-pentanoyl)-hydrazinecarboxylate

A 5 N sodium hydroxide solution (2.5 ml) was added to a solution ofmethyl 5-chloro-2-cyclohexyl-valerate (1.00 g) in THF (3 ml)-methanol (6ml). The reaction solution was stirred at room temperature for six hoursand at 60° C. for further two hours. After allowing the reactionsolution to cool, water and diethyl ether were added to the reactionsolution, and the aqueous layer was separated. 5 N hydrochloric acid(2.6 ml) and ethyl acetate were added to the aqueous layer, and theorganic layer was separated. The ethyl acetate extraction layer waswashed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (heptane-ethyl acetate system) toobtain 5-chloro-2-cyclohexyl-valeric acid (287 mg).

IPEA (0.68 ml) and BOPCl (496 mg) were added to a solution of5-chloro-2-cyclohexyl-valeric acid (285 mg) and tert-butyl carbazate(215 mg) in methylene chloride (2.5 ml), and the reaction solution wasstirred at room temperature for 5.5 hours. Ethyl acetate and water wereadded to the reaction solution, and the organic layer was separated. Theorganic layer was sequentially washed with 1 N hydrochloric acid, water,a saturated sodium bicarbonate solution and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 156 mg of thetitle compound. The property values of the compound are as follows.

ESI-MS; m/z 355 [M⁺+Na]. ¹H-NMR (CDCl₃) δ (ppm): 0.90-1.32 (m, 6H), 1.47(s, 9H), 1.50-1.94 (m, 1H), 3.46-3.61 (m, 2H), 6.46 (brs, 1H), 7.14(brs, 1H).

Synthesis of 5-chloro-2-cyclohexyl-valeric acid hydrazide hydrochloride

tert-Butyl N′-(5-chloro-2-cyclohexyl-pentanoyl)-hydrazinecarboxylate(155 mg) was dissolved in a solution of 4 N hydrogen chloride in dioxane(2 ml), and the reaction solution was stirred at room temperature forone hour. The reaction solution was concentrated under reduced pressureto obtain 144 mg of the title compound. The property value of thecompound is as follows.

ESI-MS; m/z 233 [M⁺+H—HCl].

Synthesis of (+) and(−)-8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of 5-chloro-2-cyclohexyl-valeric acid hydrazide hydrochloride(144 mg) and TEA (0.32 ml) in ethanol (1 ml) was added to a solution ofethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride obtained in Example 1 (167 mg) and TEA (0.32 ml) inethanol (1.6 ml), and the reaction solution was stirred at 70° C. fortwo days. The reaction solution was left to cool to room temperature.Then, ethyl acetate and water were added to the reaction solution, andthe organic layer was separated. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (carrier: Chromatorex™ NH; elution solvent:heptane-ethyl acetate system) and again purified by silica gel columnchromatography (elution solvent: ethyl acetate-methanol system) toobtain 27 mg of racemic8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.Then, the racemate was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: 20% ethanol-hexane)to obtain the title optically active compound with a retention time of16 minutes and positive optical rotation (11.0 mg; 100% ee) and thetitle optically active compound with a retention time of 39 minutes andnegative optical rotation (10.2 mg; 100% ee).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 418 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.07-1.54 (m, 7H),1.66-1.85 (m, 4H), 1.90-2.06 (m, 2H), 2.13-2.25 (m, 2H), 2.30 (s, 3H),2.84-2.92 (m, 1H), 3.88 (s, 3H), 4.01-4.11 (m, 1H), 4.16-4.24 (m, 1H),6.91 (s, 1H), 7.06 (d, J=16.4 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H),7.19 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.4 Hz, 1H),7.69 (s, 1H).

The property values of the title optically active compound with aretention time of 39 minutes are as follows.

ESI-MS; m/z 418 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.07-1.54 (m, 7H),1.66-1.85 (m, 4H), 1.90-2.06 (m, 2H), 2.13-2.25 (m, 2H), 2.30 (s, 3H),2.84-2.92 (m, 1H), 3.88 (s, 3H), 4.01-4.11 (m, 1H), 4.16-4.24 (m, 1H),6.91 (s, 1H), 7.06 (d, J=16.4 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H),7.19 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.4 Hz, 1H),7.69 (s, 1H).

Example 115 Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butyl (2-oxopiperidin-1-yl)carbamate

A 4 N sodium hydroxide solution (4 ml) and 5-bromo-valeryl chloride (CASNo. 4509-90-4, 1.06 ml) were added to a solution of tert-butyl carbazate(CAS No. 870-46-2, 1 g) in methylene chloride (10 ml) under ice-cooling.The reaction solution was stirred at the same temperature for 40minutes, and then the organic layer was separated. The organic layer wassequentially washed with water and brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (carrier:Chromatorex™ NH; elution solvent: ethyl acetate) to obtain 2.03 g of acarbazide compound.

Potassium tert-butoxide (850 mg) was added to a solution of thecarbazide compound (2.03 g) in THF (30 ml) under ice-cooling. Thereaction solution was stirred at the same temperature for 30 minutes andat room temperature for further 1.5 hours. Ethyl acetate and water wereadded to the reaction solution, and the organic layer was separated. Theorganic layer was sequentially washed with water and brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain907 mg of the title compound. The property values of the compound are asfollows.

ESI-MS; m/z 237 [M⁺Na]. ¹H-NMR (CDCl₃) δ (ppm): 1.48 (s, 9H), 1.78-1.96(m, 4H), 2.47 (t, J=6.4 Hz, 2H), 3.58 (t, J=6.0 Hz, 2H), 6.66 (brs, 1H).

Synthesis of 1-aminopiperidin-2-one hydrochloride

tert-Butyl (2-oxopiperidin-1-yl)carbamate (129 mg) was dissolved in asolution of 4 N hydrogen chloride in dioxane (2 ml), and the reactionsolution was stirred at room temperature for one hour. The reactionsolution was concentrated under reduced pressure to obtain 92 mg of thetitle compound. The property values of the compound are as follows.

¹H-NMR (DMSO-D₆) δ (ppm): 1.69-1.77 (m, 2H), 1.82-1.90 (m, 2H), 2.41 (t,J=6.4 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H).

Synthesis of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxopiperidin-1-yl)acrylamide

IPEA (0.26 ml), HOBT (121 mg) and EDC (172 mg) were sequentially addedto a suspension of 1-aminopiperidin-2-one hydrochloride (92 mg) and(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (CASNo. 870839-41-1, 150 mg) in DMF (4 ml), and the reaction solution wasstirred at room temperature overnight. Ethyl acetate and water wereadded to the reaction solution, and the organic layer was separated. Theorganic layer was sequentially washed with a saturated sodiumbicarbonate solution and brine. The combined aqueous layers werereextracted with ethyl acetate (twice). The combined organic layers weredried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was triturated with ethyl acetate toobtain 97 mg of the title compound. The property values of the compoundare as follows.

ESI-MS; m/z 355 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.87-2.04 (m, 4H), 2.30(s, 3H), 2.56 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.86 (s, 3H),6.47 (d, J=16.0 Hz, 1H), 6.92 (s, 1H), 7.00 (s, 1H), 7.04 (d, J=8.0 Hz,1H), 7.20 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.72 (s, 1H), 9.03(brs, 1H).

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A suspension of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxopiperidin-1-yl)acrylamide(96 mg) in phosphorus oxychloride (1 ml) was stirred at 150° C. for 1.5hours. Phosphorus oxychloride was evaporated from the reaction solutionunder reduced pressure. Glacial acetic acid (3 ml) and ammonium acetate(630 mg) were added to the resulting residue, and the reaction solutionwas stirred at 130° C. for three hours. The reaction solution was leftto cool to room temperature and then concentrated under reducedpressure. Ethyl acetate, water and a saturated sodium bicarbonatesolution were added to the resulting residue, and then the organic layerwas separated. The resulting organic layer was washed with brine, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethylacetate system) to obtain 20 mg of the title compound. The propertyvalues of the compound are as follows.

ESI-MS; m/z 336 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.97-2.16 (m, 4H), 2.30(s, 3H), 2.95 (t, J=6.4 Hz, 2H), 3.88 (s, 3H), 4.17 (t, J=6.0 Hz, 2H),6.91 (s, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.14-7.20 (m, 2H), 7.23 (d, J=8.0Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.69 (s, 1H).

Examples 116 and 117 Synthesis of (−) and(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of ethyl 5-chloro-2-(tetrahydropyran-4-yl)-valerate

672 mg of the title compound was obtained from ethyl(tetrahydropyran-4-yl)acetate (CAS No. 103260-44-2, 650 mg) and1-chloro-3-iodopropane (0.61 ml) according to the method in Example 113.The property value of the compound is as follows.

ESI-MS; m/z 249 [M⁺+H].

Synthesis of tert-butylN′-[5-chloro-2-(tetrahydropyran-4-yl)-pentanoyl]-hydrazinecarboxylate

A 5 N sodium hydroxide solution (1.6 ml) was added to a solution ofethyl 5-chloro-2-(tetrahydropyran-4-yl)-valerate (672 mg) in THF (2.5ml)-ethanol (7.5 ml), and the reaction solution was stirred at roomtemperature for four days. Water and diethyl ether were added to thereaction solution, and the aqueous layer was separated. The aqueouslayer was washed with diethyl ether again. Then, 5 N hydrochloric acid(1.6 ml) and ethyl acetate were added to the aqueous layer, and theorganic layer was separated. The ethyl acetate extraction layer waswashed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure to obtain crude5-chloro-2-(tetrahydropyran-4-yl)valeric acid (442 mg).

IPEA (1.03 ml) and BOPCl (756 mg) were added to a solution of the crude5-chloro-2-(tetrahydropyran-4-yl)valeric acid (442 mg) and tert-butylcarbazate (357 mg) in methylene chloride (7 ml), and the reactionsolution was stirred at room temperature overnight. Ethyl acetate andwater were added to the reaction solution, and the organic layer wasseparated. The organic layer was sequentially washed with 1 Nhydrochloric acid, water, a saturated sodium bicarbonate solution andbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The resulting residue was triturated with ethylacetate to obtain 250 mg of the title compound. The property values ofthe compound are as follows.

ESI-MS; m/z 357 [M⁺+Na]. ¹H-NMR (CDCl₃) δ (ppm): 1.28-1.44 (m, 2H),1.44-1.54 (m, 1H), 1.45 (s, 9H), 1.60-1.83 (m, 7H), 3.30-3.41 (m, 2H),3.46-3.60 (m, 2H), 3.91-4.03 (m, 2H), 6.43 (brs, 1H), 7.17 (brs, 1H).

Synthesis of 5-chloro-2-(tetrahydropyran-4-yl)-valeric acid hydrazidehydrochloride

tert-ButylN′-[5-chloro-2-(tetrahydropyran-4-yl)-pentanoyl]-hydrazinecarboxylate(250 mg) was dissolved in a solution of 4 N hydrogen chloride in dioxane(2 ml), and the reaction solution was stirred at room temperature for2.5 hours. The reaction solution was concentrated under reduced pressureto obtain 215 mg of the title compound. The property value of thecompound is as follows.

ESI-MS; m/z 235 [M⁺+H—HCl].

Synthesis of (−) and(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

70 mg of racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridinewas obtained according to the method in Example 113 from ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride obtained in Example 1 (300 mg) and5-chloro-2-(tetrahydropyran-4-yl)-valeric acid hydrazide hydrochloride(215 mg). Then, the racemate was separated by CHIRALPAK™ AD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain the title optically active compound with aretention time of 29 minutes and negative optical rotation (22.7 mg;100% ee) and the title optically active compound with a retention timeof 41 minutes and positive optical rotation (21.3 mg; 99% ee).

The property values of the title optically active compound with aretention time of 29 minutes are as follows.

ESI-MS; m/z 420 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.40-1.1.48 (m, 1H),1.52-1.83 (m, 4H), 1.95-2.10 (m, 2H), 2.18-2.28 (m, 1H), 2.30 (d, J=0.8Hz, 3H), 2.33-2.46 (m, 1H), 2.87-2.95 (m, 1H), 3.42-3.53 (m, 2H), 3.88(s, 3H), 3.97-4.12 (m, 3H), 4.17-4.26 (m, 1H), 6.92 (dd, J=1.2, 0.8 Hz,1H), 7.06 (d, J=16.4 Hz, 1H), 7.15-7.20 (m, 2H), 7.23 (d, J=8.4 Hz, 1H),7.53 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 41 minutes are as follows.

ESI-MS; m/z 420 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.40-1.1.48 (m, 1H),1.52-1.83 (m, 4H), 1.95-2.10 (m, 2H), 2.18-2.28 (m, 1H), 2.30 (s, 3H),2.33-2.46 (m, 1H), 2.87-2.95 (m, 1H), 3.42-3.53 (m, 2H), 3.88 (s, 3H),3.97-4.12 (m, 3H), 4.17-4.26 (m, 1H), 6.92 (d, J=1.2 Hz, 1H), 7.06 (d,J=16.4 Hz, 1H), 7.15-7.20 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.53 (d,J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Examples 118 and 119 Synthesis of (+) and(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butyl4-(4-chloro-1-ethoxycarbonyl-butan-1-yl)piperidine-1-carboxylate

1.76 g of the title compound was obtained from tert-butyl4-ethoxycarbonylmethyl-piperidine-1-carboxylate (CAS No. 142851-03-4,1.95 g) and 1-chloro-3-iodopropane (1.16 ml) according to the method inExample 113. The property value of the compound is as follows.

ESI-MS; m/z 370 [M⁺+Na].

Synthesis of tert-butyl4-[1-(N′-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]piperidine-1-carboxylate

A 5 N sodium hydroxide solution (3 ml) was added to a solution oftert-butyl4-(4-chloro-1-ethoxycarbonyl-butan-1-yl)piperidine-1-carboxylate (1.76g) in THF (5 ml)-ethanol (15 ml), and the reaction solution was stirredat room temperature for four days. Water and diethyl ether were added tothe reaction solution, and the aqueous layer was separated. The aqueouslayer was washed with diethyl ether again. Then, 5 N hydrochloric acid(3 ml) and ethyl acetate were added to the aqueous layer, and theorganic layer was separated. The ethyl acetate extraction layer waswashed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure to obtain crude tert-butyl4-(1-carboxy-4-chlorobutan-1-yl)piperidine-1-carboxylate (1.25 g).

IPEA (2.0 ml) and BOPCl (1.55 g) were added to a solution of the crudetert-butyl 4-(1-carboxy-4-chlorobutan-1-yl)piperidine-1-carboxylate(1.25 g) and benzyl carbazate (CAS No. 5331-43-1, 883 mg) in methylenechloride (15 ml), and the reaction solution was stirred at roomtemperature overnight. Ethyl acetate and water were added to thereaction solution, and the organic layer was separated. The organiclayer was sequentially washed with 1 N hydrochloric acid, water, asaturated sodium bicarbonate solution and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 928 mg of thetitle compound. The property value of the compound is as follows.

ESI-MS; m/z 490 [M⁺+Na].

Synthesis of tert-butyl4-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]piperidine-1-carboxylate

10% palladium-carbon (50% wet, 200 mg) was added to a solution oftert-butyl4-[1-(N′-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]piperidine-1-carboxylate(928 mg) in methanol (15 ml), and the reaction solution was hydrogenatedat normal pressure at room temperature for 4.5 hours. The catalyst isremoved by filtration and the filtrate is concentrated under reducedpressure to obtain 663 mg of the title compound. The property value ofthe compound is as follows.

ESI-MS; m/z 356[M⁺+Na].

Synthesis of tert-butyl4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidine-1-carboxylate

A solution of tert-butyl4-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]piperidine-1-carboxylate (663mg) in 1-propanol (4 mL) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride obtained in Example 1 (792 mg) and TEA (1.7 mL) in1-propanol (16 mL), and the reaction solution was stirred at 90° C.overnight. The reaction solution was left to cool to room temperatureand then concentrated under reduced pressure. Ethyl acetate, water and asaturated sodium bicarbonate solution were added to the concentrationresidue, and the organic layer was separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (carrier: Chromatorex™ NH; elutionsolvent: heptane-ethyl acetate system) to obtain 361 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 519[M⁺+H].

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Trifluoroacetic acid (1 ml) was added to a solution of tert-butyl4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidine-1-carboxylate(361 mg) in methylene chloride (3 ml), and the mixture was stirred atroom temperature for two hours. A saturated sodium bicarbonate solutionand ethyl acetate were added to the reaction solution, and the organiclayer was separated. The organic layer was sequentially washed with asaturated sodium bicarbonate solution and brine. Since most of thetarget compound was present in the aqueous layers, the combined aqueouslayers were extracted with methylene chloride three times. The methylenechloride extraction layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (carrier: Chromatorex™ NH;elution solvent: chloroform-methanol system) to obtain 166 mg of thetitle compound. The property values of the compound are as follows.

ESI-MS; m/z 419 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.34-1.56 (m, 3H),1.72-1.83 (m, 2H), 1.93-2.09 (m, 2H), 2.16-2.36 (m, 2H), 2.30 (d, J=1.2Hz, 3H), 2.63-2.75 (m, 2H), 2.87-2.93 (m, 1H), 3.06-3.20 (m, 2H), 3.88(s, 3H), 4.02-4.12 (m, 1H), 4.17-4.25 (m, 1H), 6.92 (t, J=1.2 Hz, 1H),7.06 (d, J=16.0 Hz, 1H), 7.15-7.20 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.53(d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Synthesis of (+) and(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(5 mg) was separated by CHIRALPAK™ OD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane) toobtain the title optically active compound with a retention time of 29minutes and positive optical rotation (1.58 mg, 100% ee) and the titleoptically active compound with a retention time of 55 minutes andnegative optical rotation (1.40 mg, 99% ee).

The property values of the title optically active compound with aretention time of 29 minutes are as follows.

ESI-MS; m/z 419 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.34-1.56 (m, 3H),1.72-1.83 (m, 2H), 1.93-2.09 (m, 2H), 2.16-2.36 (m, 2H), 2.30 (d, J=1.2Hz, 3H), 2.63-2.75 (m, 2H), 2.87-2.93 (m, 1H), 3.06-3.20 (m, 2H), 3.88(s, 3H), 4.02-4.12 (m, 1H), 4.17-4.25 (m, 1H), 6.92 (t, J=1.2 Hz, 1H),7.06 (d, J=16.0 Hz, 1H), 7.15-7.20 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.53(d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 55 minutes are as follows.

ESI-MS; m/z 419 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.34-1.56 (m, 3H),1.72-1.83 (m, 2H), 1.93-2.09 (m, 2H), 2.16-2.36 (m, 2H), 2.30 (d, J=1.2Hz, 3H), 2.63-2.75 (m, 2H), 2.87-2.93 (m, 1H), 3.06-3.20 (m, 2H), 3.88(s, 3H), 4.02-4.12 (m, 1H), 4.17-4.25 (m, 1H), 6.92 (t, J=1.2 Hz, 1H),7.06 (d, J=16.0 Hz, 1H), 7.15-7.20 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.53(d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Examples 120 and 121 Synthesis of (+) and(−)-1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]ethanone

A 1 N sodium hydroxide solution (0.5 ml) and acetyl chloride (14 ul)were added to a solution of racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Examples 118 and 119 (25 mg) in methylene chloride (0.5 ml),and the reaction solution was stirred at room temperature for 40minutes. Chloroform was added to the reaction solution, and the organiclayer was separated. The aqueous layer was reextracted with chloroformtwice. The combined organic layers were dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to obtain 25 mg ofracemic1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]ethanone.Then, the racemate was separated by CHIRALPAK™ IA manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtainthe title optically active compound with a retention time of 27 minutesand positive optical rotation (7.4 mg; 100% ee) and the title opticallyactive compound with a retention time of 34 minutes and negative opticalrotation (6.7 mg; 97% ee)

The property values of the title optically active compound with aretention time of 27 minutes are as follows.

ESI-MS; m/z 461 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.30-1.85 (m, 3H),1.88-2.65 (m, 7H), 2.09 and 2.11 (each s, 3H), 2.30 (s, 3H), 2.88-3.01(m, 1H), 3.05-3.16 (m, 1H), 3.80-3.95 (m, 1H), 3.88 (s, 3H), 4.01-4.13(m, 1H), 4.18-4.28 (m, 1H), 4.66-4.80 (m, 1H), 6.92 (s, 1H), 7.06 (d,J=16.0 Hz, 1H), 7.15-7.20 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.52 (d,J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 34 minutes are as follows.

ESI-MS; m/z 461 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.30-1.85 (m, 3H),1.88-2.65 (m, 7H), 2.09 and 2.11 (each s, 3H), 2.30 (s, 3H), 2.88-3.01(m, 1H), 3.05-3.16 (m, 1H), 3.80-3.95 (m, 1H), 3.88 (s, 3H), 4.01-4.13(m, 1H), 4.18-4.28 (m, 1H), 4.66-4.80 (m, 1H), 6.92 (s, 1H), 7.06 (d,J=16.0 Hz, 1H), 7.15-7.20 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.52 (d,J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Examples 122 and 123 Synthesis of (+) and(−)-8-(1-isopropylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Acetone (16 μl) and glacial acetic acid (17 μl) were added to a solutionof racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Examples 118 and 119 (30 mg) in THF (3 ml), and the reactionsolution was stirred at room temperature for 30 minutes. Sodiumtriacetoxyhydroborate (46 mg) was added to the reaction solution, andthe reaction solution was stirred at room temperature for 1.5 hours.Acetone (80 μl) and sodium triacetoxyhydroborate (184 mg) were added tothe reaction solution, and the reaction solution was stirred at roomtemperature overnight. A saturated sodium bicarbonate solution and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The organic layer was sequentially washed with water andbrine and dried over anhydrous magnesium sulfate.

On the other hand, cesium carbonate (47 μl) was added to a solution ofracemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(20 mg) and 2-iodopropane (15 μl) in DMF (1 ml), and the reactionsolution was stirred at room temperature overnight. The reactionsolution was concentrated under reduced pressure. Water and ethylacetate were added to the residue, and the organic layer was separated.The organic layer was washed with brine and dried over anhydrousmagnesium sulfate.

At this time, the organic layer was combined with the after-treatmentsolution in the above experiment, and the layers were concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (carrier: Chromatorex™ NH; elution solvent: ethylacetate) and again purified by silica gel column chromatography (elutionsolvent: ethyl acetate-methanol system) to obtain 21 mg of racemic8-(1-isopropylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.Then, the racemate was separated by CHIRALCEL™ OD-H manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 40%ethanol-hexane) to obtain the title optically active compound with aretention time of 9 minutes and positive optical rotation (4.61 mg; 100%ee) and the title optically active compound with a retention time of 15minutes and negative optical rotation (4.83 mg; 99% ee).

The property values of the title optically active compound with aretention time of 9 minutes are as follows.

ESI-MS; m/z 461 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.06 (s, 3H), 1.07 (s,3H), 1.40-1.56 (m, 3H), 1.70-1.88 (m, 2H), 1.91-2.09 (m, 2H), 2.13-2.35(m, 4H), 2.30 (s, 3H), 2.68-2.80 (m, 1H), 2.88-3.04 (m, 3H), 3.88 (s,3H), 4.02-4.12 (m, 1H), 4.17-4.25 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.0Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d,J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 15 minutes are as follows.

ESI-MS; m/z 461 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.06 (s, 3H), 1.07 (s,3H), 1.40-1.56 (m, 3H), 1.70-1.88 (m, 2H), 1.91-2.09 (m, 2H), 2.13-2.35(m, 4H), 2.30 (s, 3H), 2.68-2.80 (m, 1H), 2.88-3.04 (m, 3H), 3.88 (s,3H), 4.02-4.12 (m, 1H), 4.17-4.25 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.0Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d,J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Examples 124 and 125 Synthesis of (+) and(−)-8-(1-benzylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Benzaldehyde (15 μl) and glacial acetic acid (16 μl) were added to asolution of racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Examples 118 and 119 (30 mg) in THF (2 ml), and the reactionsolution was stirred at room temperature for 30 minutes. Sodiumtriacetoxyhydroborate (46 mg) was added to the reaction solution, andthe reaction solution was stirred at room temperature for four hours. Asaturated sodium bicarbonate solution and ethyl acetate were added tothe reaction solution, and the organic layer was separated. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (carrier: Chromatorex™ NH; elutionsolvent: ethyl acetate) to obtain 27 mg of racemic8-(1-benzylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.Then, the racemate was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane)to obtain the title optically active compound with a retention time of14 minutes and positive optical rotation (9.4 mg; >99% ee) and the titleoptically active compound with a retention time of 20 minutes andnegative optical rotation (8.9 mg; 99% ee).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

ESI-MS; m/z 509 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.40-1.70 (m, 3H),1.72-1.82 (m, 2H), 1.90-2.10 (m, 4H), 2.12-2.25 (m, 2H), 2.30 (d, J=1.2Hz, 3H), 2.87-3.01 (m, 3H), 3.51 (d, J=13.2 Hz, 1H), 3.53 (d, J=13.2 Hz,1H), 3.88 (s, 3H), 4.02-4.11 (m, 1H), 4.16-4.25 (m, 1H), 6.91 (t, J=1.2Hz, 1H), 7.05 (d, J=16.0 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.18 (d,J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.23-7.35 (m, 5H), 7.51 (d,J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 20 minutes are as follows.

ESI-MS; m/z 509 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.40-1.70 (m, 3H),1.72-1.82 (m, 2H), 1.90-2.10 (m, 4H), 2.12-2.25 (m, 2H), 2.30 (d, J=1.2Hz, 3H), 2.87-3.01 (m, 3H), 3.51 (d, J=13.2 Hz, 1H), 3.53 (d, J=13.2 Hz,1H), 3.88 (s, 3H), 4.02-4.11 (m, 1H), 4.16-4.25 (m, 1H), 6.91 (t, J=1.2Hz, 1H), 7.05 (d, J=16.0 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.18 (d,J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.23-7.35 (m, 5H), 7.51 (d,J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Examples 126 and 127 Synthesis of (+) and(−)-1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]phenylmethanone

A 1 N sodium hydroxide solution (0.5 ml) and benzoyl chloride (11 ul)were added to a solution of racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Examples 118 and 119 (20 mg) in methylene chloride (1 ml),and the reaction solution was stirred under ice-cooling for four hours.Methylene chloride was added to the reaction solution, and the organiclayer was separated. The aqueous layer was reextracted with methylenechloride. The combined organic layers were dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtain 19mg of racemic1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]phenylmethanone.Then, the racemate was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane)to obtain the title optically active compound with a retention time of16 minutes and positive optical rotation (6.9 mg; 100% ee) and the titleoptically active compound with a retention time of 22 minutes andnegative optical rotation (6.8 mg; >99% ee).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 523 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.30-2.14 (m, 6H),2.17-2.28 (m, 2H), 2.30 (s, 3H), 2.33-2.58 (m, 1H), 2.70-3.15 (m, 3H),3.73-3.95 (m, 1H), 3.88 (s, 3H), 4.00-4.16 (m, 1H), 4.18-4.28 (m, 1H),4.70-4.95 (m, 1H), 6.92 (s, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.14-7.20 (m,2H), 7.22 (d, J=8.0 Hz, 1H), 7.40 (s, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70(d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 22 minutes are as follows.

ESI-MS; m/z 523 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.30-2.14 (m, 6H),2.17-2.28 (m, 2H), 2.30 (s, 3H), 2.33-2.58 (m, 1H), 2.70-3.15 (m, 3H),3.73-3.95 (m, 1H), 3.88 (s, 3H), 4.00-4.16 (m, 1H), 4.18-4.28 (m, 1H),4.70-4.95 (m, 1H), 6.92 (s, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.14-7.20 (m,2H), 7.22 (d, J=8.0 Hz, 1H), 7.40 (s, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70(d, J=1.2 Hz, 1H).

Examples 128 and 129 Synthesis of (+) and(−)-8-(1-benzenesulfonylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

TEA (20 μl) and benzenesulfonyl chloride (8 μl) were added to a solutionof racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Examples 118 and 119 (20 mg) in methylene chloride (1 ml),and the reaction solution was stirred at room temperature for 40minutes. Water and ethyl acetate were added to the reaction solution,and the organic layer was separated. The organic layer was sequentiallywashed with a saturated sodium bicarbonate solution and brine, driedover anhydrous magnesium sulfate and concentrated under reduced pressureto obtain 24 mg of racemic8-(1-benzenesulfonylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.Then, the racemate was separated by CHIRALCEL™ OD-H manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) toobtain the title optically active compound with a retention time of 24minutes and positive optical rotation (7.3 mg; 100% ee) and the titleoptically active compound with a retention time of 29 minutes andnegative optical rotation (7.4 mg; >98% ee).

The property values of the title optically active compound with aretention time of 24 minutes are as follows.

ESI-MS; m/z 559 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.50-1.76 (m, 3H),1.82-2.37 (m, 8H), 2.30 (d, J=1.2 Hz, 3H), 2.87-2.95 (m, 1H), 3.80-3.96(m, 2H), 3.87 (s, 3H), 4.00-4.10 (m, 1H), 4.17-4.27 (m, 1H), 6.91 (t,J=1.2 Hz, 1H), 7.01 (d, J=16.0 Hz, 1H), 7.13 (dd, J=8.0, 1.2 Hz, 1H),7.16 (d, J=1.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H),7.53 (td, J=7.2, 1.2 Hz, 2H), 7.61 (tt, J=7.2, 1.2 Hz, 1H), 7.69 (d,J=1.2 Hz, 1H), 7.76 (dt, J=8.0, 1.2 Hz, 2H).

The property values of the title optically active compound with aretention time of 29 minutes are as follows.

ESI-MS; m/z 559 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.50-1.76 (m, 3H),1.82-2.37 (m, 8H), 2.30 (d, J=1.2 Hz, 3H), 2.87-2.95 (m, 1H), 3.80-3.96(m, 2H), 3.87 (s, 3H), 4.00-4.10 (m, 1H), 4.17-4.27 (m, 1H), 6.91 (t,J=1.2 Hz, 1H), 7.01 (d, J=16.0 Hz, 1H), 7.13 (dd, J=8.0, 1.2 Hz, 1H),7.16 (d, J=1.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H),7.53 (td, J=7.2, 1.2 Hz, 2H), 7.61 (tt, J=7.2, 1.2 Hz, 1H), 7.69 (d,J=1.2 Hz, 1H), 7.76 (dt, J=8.0, 1.2 Hz, 2H).

Examples 130, 131, 132 and 133 Synthesis of (−), (+), (+) and(−)-8-(1-benzylpyrrolidin-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butyl2-methoxycarbonylmethyl-pyrrolidine-1-carboxylate

Trimethylsilyldiazomethane (2 M solution in hexane, 1.5 ml) was addeddropwise to a mixed solution of tert-butyl2-carboxymethylpyrrolidine-1-carboxylate (CAS No. 194154-91-1, 500 mg)in methanol (1 ml)-toluene (1 ml) under ice-cooling, and the reactionsolution was stirred at the same temperature for three hours. Thereaction solution was concentrated. The resulting residue was purifiedby silica gel column chromatography (elution solvent: heptane-ethylacetate system) to obtain 506 mg of the title compound. The propertyvalues of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.46 (s, 9H), 1.67-1.90 (m, 3H), 1.98-2.12 (m,1H), 2.30 (dd, J=15.2, 10.0 Hz, 1H), 2.75-3.02 (m, 1H), 3.26-3.45 (m,2H), 3.67 (s, 3H), 4.04-4.25 (m, 1H)

Synthesis of tert-butyl2-(4-chloro-1-methoxycarbonyl-butan-1-yl)pyrrolidine-1-carboxylate

335 mg of the title compound was obtained from tert-butyl2-methoxycarbonylmethyl-pyrrolidine-1-carboxylate (506 mg) and1-chloro-3-iodopropane (335 μl) according to the method in Example 113.The property value of the compound is as follows.

ESI-MS; m/z 342 [M⁺+Na].

Synthesis of tert-butyl2-[1-(N′-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]pyrrolidine-1-carboxylate

142 mg of the title compound was obtained from tert-butyl2-(4-chloro-1-methoxycarbonyl-butan-1-yl)pyrrolidine-1-carboxylate (335mg) according to the method in Example 118. The property value of thecompound is as follows.

ESI-MS; m/z 476 [M⁺+Na].

Synthesis of tert-butyl2-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]pyrrolidine-1-carboxylate

107 mg of the title compound was obtained from tert-butyl2-[1-(N′-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]pyrrolidine-1-carboxylate(142 mg) according to the method in Example 118. The property value ofthe compound is as follows.

ESI-MS; m/z 342 [M⁺+Na].

Synthesis of tert-butyl2-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyrrolidine-1-carboxylate

56 mg of the title compound was obtained from ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (125 mg) and tert-butyl2-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]pyrrolidine-1-carboxylate(107 mg) according to the method in Example 118. The property value ofthe compound is as follows.

ESI-MS; m/z 505 [M⁺+H].

Synthesis of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyrrolidin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

24 mg of the title compound was obtained from tert-butyl2-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyrrolidine-1-carboxylate(56 mg) according to the method in Example 118. The property value ofthe compound is as follows.

ESI-MS; m/z 405 [M⁺+H].

Synthesis of (−), (+), (+) and(−)-8-(1-benzylpyrrolidin-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

8 mg of a diastereomer mixture,8-(1-benzylpyrrolidin-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,was obtained from2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyrrolidin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(10 mg) according to the method in Example 124. The diastereomer mixturewas separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: 100% ethanol) to obtain thetitle optically active compound with a retention time of 26 minutes andnegative optical rotation (1.43 mg; >96% ee). Then, the diastereomermixture with a retention time of 19.5 to 23 minutes in the AD-H columnwas separated again by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane) toobtain the title optically active compound with a retention time of 7.5minutes and positive optical rotation (0.90 mg; >99% ee), the titleoptically active compound with a retention time of 8 minutes andpositive optical rotation (1.75 mg; >99% ee) and the title opticallyactive compound with a retention time of 14 minutes and negative opticalrotation (8.9 mg; 99% ee).

The property values of the title optically active compound with aretention time of 26 minutes in the AD-H column are as follows.

ESI-MS; m/z 495 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.70-1.79 (m, 2H),1.84-2.35 (m, 7H), 2.30 (s, 3H), 2.91-2.98 (m, 1H), 3.02-3.09 (m, 1H),3.23 (d, J=13.2 Hz, 1H), 3.52 (d, J=13.2 Hz, 1H), 3.57-3.64 (m, 1H),3.87 (s, 3H), 3.99-4.08 (m, 1H), 4.14-4.23 (m, 1H), 6.91 (s, 1H), 7.04(d, J=16.0 Hz, 1H), 7.12-7.26 (m, 8H) 7.52 (d, J=16.0 Hz, 1H), 7.69 (d,J=0.8 Hz, 1H).

The property values of the title optically active compound with aretention time of 7.5 minutes in the IB column are as follows.

ESI-MS; m/z 495 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.25-1.40 (m, 1H),1.55-2.02 (m, 5H), 2.16-2.37 (m, 3H), 2.30 (s, 3H), 2.95-3.03 (m, 1H),3.22-3.30 (m, 1H), 3.37 (d, J=13.2 Hz, 1H), 3.50-3.60 (m, 1H), 3.88 (s,3H), 4.00-4.11 (m, 2H), 4.24-4.31 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.4Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d,J=8.0 Hz, 1H), 7.25-7.40 (m, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70 (d,J=1.6 Hz, 1H).

The property values of the title optically active compound with aretention time of 8 minutes in the IB column are as follows.

ESI-MS; m/z 495 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.70-1.79 (m, 2H),1.84-2.35 (m, 7H), 2.30 (s, 3H), 2.91-2.98 (m, 1H), 3.02-3.09 (m, 1H),3.23 (d, J=13.2 Hz, 1H), 3.52 (d, J=13.2 Hz, 1H), 3.57-3.64 (m, 1H),3.87 (s, 3H), 3.99-4.08 (m, 1H), 4.14-4.23 (m, 1H), 6.91 (s, 1H), 7.04(d, J=16.0 Hz, 1H), 7.12-7.26 (m, 8H) 7.52 (d, J=16.0 Hz, 1H), 7.69 (d,J=0.8 Hz, 1H).

The property values of the title optically active compound with aretention time of 14 minutes in the IB column are as follows.

ESI-MS; m/z 495 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.25-1.40 (m, 1H),1.55-2.02 (m, 5H), 2.16-2.37 (m, 3H), 2.30 (s, 3H), 2.95-3.03 (m, 1H),3.22-3.30 (m, 1H), 3.37 (d, J=13.2 Hz, 1H), 3.50-3.60 (m, 1H), 3.88 (s,3H), 4.00-4.11 (m, 2H), 4.24-4.31 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.4Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d,J=8.0 Hz, 1H), 7.25-7.40 (m, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70 (d,J=1.6 Hz, 1H).

Examples 134 and 135 Synthesis of erythro- andthreo-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(1-phenylpyrrolidin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Bromobenzene (12 ul) was added to a solution of2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyrrolidin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Examples 130, 131, 132 and 133 (15 mg),tris(dibenzylideneacetone)dipalladium (0) (7 mg),bis(diphenylphosphino)-1,1-binaphthalene (10 mg) and sodiumtert-butoxide (13 mg) in toluene (3 ml)-dioxane (1 ml). The reactionsolution was stirred at an external temperature of 100° C. overnight.Tris(dibenzylideneacetone)dipalladium (0) (7 mg),bis(diphenylphosphino)-1,1-binaphthalene (10 mg), sodium tert-butoxide(13 mg) and bromobenzene (12 ul) were added to the reaction solution,and the reaction solution was heated for further nine hours. Afterleaving the reaction solution to cool, ethyl acetate and water wereadded to the reaction solution and the organic layer was separated. Theresulting organic layer was washed with brine, dried over anhydrousmagnesium sulfate and then evaporated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetatesystem) to obtain 10.3 mg of a diastereomer mixture of the titlecompound.

The mixture was separated by LC-MS. A saturated sodium bicarbonatesolution and ethyl acetate were added to each of the resultingdiastereomers, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure to obtain 0.35 mgof the title compound with a short retention time in LC-MS and 0.25 mgof the title compound with a long retention time in LC-MS.

The property value of the title diastereomer with a short retention timein LC-MS is as follows.

ESI-MS; m/z 481 [M⁺+H].

The property value of the title diastereomer with a long retention timein LC-MS is as follows.

ESI-MS; m/z 481 [M⁺+H].

Examples 136, 137, 138 and 139 Synthesis of (+), (+), (−) and(−)-8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of methyl 2-(6,6-dimethyltetrahydropyran-2-yl)acetate

Cerium chloride heptahydrate (812 mg) and sodium iodide (327 mg) wereadded to a solution of methyl 3-hydroxy-7-methyl-6-octenoate obtained bythe method described in Heterocycles, 34, 1107-1117 (1992) (4.06 g) inacetonitrile (10 ml), and the reaction solution was heated under refluxfor 10 hours. The reaction solution was left to cool and thenconcentrated under reduced pressure. Diethyl ether and 12 ml of 1 Nhydrochloric acid were added to the resulting residue, and the organiclayer was separated. Diethyl ether was added to the aqueous layer, andthe organic layer was separated. The combined organic layers weresequentially washed with water, a saturated sodium bicarbonate solution(pH=9), a 5% sodium thiosulfate solution, water and brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain2.65 g of the title compound. The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.08-1.48 (m, 3H), 1.18 (s, 3H), 1.20 (s, 3H),1.57-1.73 (m, 3H), 2.34 (dd, J=14.8, 6.0 Hz, 1H), 2.48 (dd, J=14.8, 7.2Hz, 1H), 3.67 (s, 3H), 3.94-4.02 (m, 1H).

Synthesis of tert-butylN′-[5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)pentanoyl]hydrazinecarboxylate

n-Butyl lithium (2.64 M solution in hexane, 1.1 ml) was added dropwiseto a solution of diisopropylamine (0.45 ml) in THF (6 ml), and thereaction solution was stirred at −30° C. for 15 minutes. The reactionsolution was cooled to −78° C. Hexamethylphosphoramide (0.75 ml) and asolution of methyl 2-(6,6-dimethyltetrahydropyran-2-yl)acetate (500 mg)in THF (3 ml) were sequentially added dropwise to the reaction solution,and the reaction solution was stirred at the same temperature for 20minutes. 1-Chloro-3-iodopropane (0.43 ml) was added dropwise to theresulting reaction solution. The reaction solution was gradually heated,and then a saturated ammonium chloride solution was added to thereaction solution. Ethyl acetate and water were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was sequentially washed with 1 N hydrochloric acid, water, asaturated sodium bicarbonate solution and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 278 mg ofmethyl 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)valerate.

39 mg of the title compound was obtained from 278 mg of methyl5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)valerate according to themethod in Example 113. The property values of the compound are asfollows.

ESI-MS; m/z 385 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.15-1.33 (m, 1H), 1.21(s, 3H), 1.23 (s, 3H), 1.36-1.57 (m, 3H), 1.47 (s, 9H), 1.58-1.98 (m,6H), 2.26-2.33 (m, 1H), 3.48-3.62 (m, 2H), 3.63-3.76 (m, 1H), 6.39 (brs,1H), 8.17 and 8.40 (each brs, 1H).

Synthesis of 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)-valeric acidhydrazide hydrochloride

36 mg of the title compound was obtained from 39 mg of tert-butylN′-[5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)pentanoyl]hydrazinecarboxylateaccording to the method in Example 113. The property value of thecompound is as follows.

ESI-MS; m/z 263 [M⁺−HCl+H].

Synthesis of (+), (+), (−) and(−)-8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

5.2 mg of a diastereomer mixture,8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,was obtained according to the method in Example 113 from ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride obtained in Example 1 (47 mg) and5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)-valeric acid hydrazidehydrochloride (36 mg). The diastereomer mixture was separated byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: 30% ethanol-hexane) to obtain the title opticallyactive compound with a retention time of 13 minutes and positive opticalrotation (0.75 mg), the title optically active compound with a retentiontime of 14 minutes and positive optical rotation (0.21 mg), the titleoptically active compound with a retention time of 16 minutes andnegative optical rotation (0.13 mg) and the title optically activecompound with a retention time of 24 minutes and negative opticalrotation (0.54 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

ESI-MS; m/z 448 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.12 (s, 3H), 1.14 (s,3H), 1.30-1.50 (m, 3H), 1.60-1.76 (m, 2H), 1.73-2.00 (m, 3H), 2.12-2.35(m, 2H), 2.30 (d, J=0.8 Hz, 3H), 2.93 (dd, J=11.6, 6.0 Hz, 1H), 3.88 (s,3H), 4.04-4.20 (m, 3H), 6.91 (brs, 1H), 7.07 (d, J=16.0 Hz, 1H), 7.16(dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H),7.51 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

ESI-MS; m/z 448 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.15-1.80 (m, 6H), 1.19(s, 3H), 1.28 (s, 3H), 1.81-2.05 (m, 2H), 2.10-2.40 (m, 2H), 2.30 (s,3H), 3.12-3.20 (m, 1H), 3.88 (s, 3H), 4.02-4.40 (m, 3H), 6.92 (brs, 1H),7.07 (d, J=16.0 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.21 (d, J=1.6Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.70 (s, 1H).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 448 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.15-1.80 (m, 6H), 1.19(s, 3H), 1.28 (s, 3H), 1.81-2.05 (m, 2H), 2.10-2.40 (m, 2H), 2.30 (s,3H), 3.12-3.20 (m, 1H), 3.88 (s, 3H), 4.02-4.40 (m, 3H), 6.92 (brs, 1H),7.07 (d, J=16.0 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.21 (d, J=1.6Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.70 (s, 1H).

The property values of the title optically active compound with aretention time of 24 minutes are as follows.

ESI-MS; m/z 448 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.12 (s, 3H), 1.14 (s,3H), 1.30-1.50 (m, 3H), 1.60-1.76 (m, 2H), 1.73-2.00 (m, 3H), 2.12-2.35(m, 2H), 2.30 (d, J=0.8 Hz, 3H), 2.93 (dd, J=11.6, 6.0 Hz, 1H), 3.88 (s,3H), 4.04-4.20 (m, 3H), 6.91 (brs, 1H), 7.07 (d, J=16.0 Hz, 1H), 7.16(dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H),7.51 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).

Examples 140 and 141 Synthesis of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazoleand(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Synthesis of 4-chloro-2-phenylbutyric acid

A 2.64 M solution of butyl lithium in hexane (28 mL) was added to asolution of phenylacetic acid (5.07 g) in THF (150 mL) in a nitrogenatmosphere at −78° C., and the reaction solution was stirred at −78° C.for 20 minutes. The reaction solution was further stirred at 0° C. forone hour. Then, 1-bromo-2-chloroethane (3.1 mL) was added at 0° C., andthe reaction solution was stirred at room temperature for 14 hours.Ethyl acetate and 1 N hydrochloric acid were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was washed with a saturated sodium chloride solution. Theresulting organic layer was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 5.54 g of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.19-2.28 (m, 1H), 2.47-2.57 (m, 1H), 3.32-3.40(m, 1H), 3.52-3.58 (m, 1H), 3.92 (dd, J=8.0, 7.2 Hz, 1H), 7.26-7.37 (m,5H).

Synthesis of(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazoleand(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at0° C., and the reaction solution was stirred at room temperature for onehour. The reaction solution was concentrated under reduced pressure toobtain 4-chloro-2-phenylbutyric acid chloride. A solution of4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to asolution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) inTHF (40 mL) at 0° C., and the reaction solution was stirred at roomtemperature for one hour. The reaction solution was added to a saturatedsodium bicarbonate solution, followed by extraction with ethyl acetate.The resulting extract was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain tert-butylN′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solutionof 4 N hydrogen chloride in ethyl acetate (50 mL) was added totert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g).The reaction solution was stirred at room temperature for one hour andthen concentrated under reduced pressure to obtain4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). Asolution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solutionof ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL)at room temperature, and the reaction solution was stirred at 80° C. for24 hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the resulting residue, followed by extraction withchloroform. The resulting extract was dried over magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system) to obtain 231 mg of the racemictitle compound. The property values of the compound are as follows.

ESI-MS; m/z 398 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=0.4 Hz, 3H),2.67-2.76 (m, 1H), 3.20-3.30 (m, 1H), 3.87 (s, 3H), 4.17-4.25 (m, 1H),4.30-4.38 (m, 1H), 4.45 (dd, J=8.8, 6.0 Hz, 1H), 6.89-6.92 (m, 1H), 7.08(d, J=16.0 Hz, 1H), 7.14-7.38 (m, 8H), 7.56 (d, J=16.0 Hz, 1H), 7.69 (d,J=1.2 Hz, 1H).

The racemic title compound (16 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=7:3) to obtain the title optically active compoundwith a retention time of 32 minutes and positive optical rotation (4 mg)and the title optically active compound with a retention time of 39minutes and negative optical rotation (6 mg).

The following compounds were obtained by the same method as in Examples140 and 141 (Table 4).

TABLE 4

Example E₃ DATA: MS m/z Note 142

M⁺ + H: 432 (ESI) Optically active compound (separation conditionsIA:ethanol: retention time 22 min, optical rotation (+)) 143

M⁺ + H: 432 (ESI) Optically active compound (separation conditionsIA:ethanol: retention time 27 min, optical rotation (−)) 144

M⁺ + H: 416 (ESI) Optically active compound (separation conditionsIA:ethanol: retention time 25 min, optical rotation (+)) 145

M⁺ + H: 416 (ESI) Optically active compound (separation conditionsIA:ethanol: retention time 28 min, optical rotation (−))

The following compounds were obtained by the same method as in Examples53 and 54 (Table 5).

TABLE 5

Example E₃ DATA: MS m/z Note 146

M⁺ + H: 414 (ESI) Optically active compound (separation conditions OJ-H,hexane:ethanol = 4:1, retention time 20 min, optical rotation (−)) 147

M⁺ + H: 414 (ESI) Optically active compound (separation conditions OJ-H,hexane:ethanol = 4:1, retention time 34 min, optical rotation (+)) 148

M⁺ + H: 432 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 4:1, retention time 31 min, optical rotation (−)) 149

M⁺ + H: 432 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 4:1, retention time 47 min, optical rotation (+)) 150

M⁺ + H: 448 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 4:1, retention time 35 min, optical rotation (−)) 151

M⁺ + H: 448 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 4:1, retention time 39 min, optical rotation (+))

The following compounds were obtained by the same method as in Examples65 and 66 (Table 6).

TABLE 6

Example E₃ DATA: MS m/z Note 152

M⁺ + H: 423 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 1:1, retention time 15 min, optical rotation (+)) 153

M⁺ + H: 423 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 1:1, retention time 18 min, optical rotation (−)) 154

M⁺ + H: 441 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 4:1, retention time 28 min, optical rotation (−)) 155

M⁺ + H: 441 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 4:1, retention time 34 min, optical rotation (+)) 156

M⁺ + H: 457 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 4:1, retention time 23 min, optical rotation (−)) 157

M⁺ + H: 457 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 4:1, retention time 32 min, optical rotation (+)) 158

M⁺ + H: 477 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 1:1, retention time 10 min, optical rotation (−)) 159

M⁺ + H: 477 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 1:1, retention time 13 min, optical rotation (+))

Examples 160 and 161 Synthesis of(−)-7-fluoro-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazoleand(+)-7-fluoro-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

DAST (0.11 mL) was added to a solution of racemic2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-olsynthesized in Examples 146 and 147 (115 mg) in methylene chloride (5mL) in a nitrogen atmosphere at 0° C., and the reaction solution wasstirred at 0° C. for one hour. A saturated sodium bicarbonate solutionwas added to the reaction solution, followed by extraction with ethylacetate. The resulting extract was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (carrier: Chromatorex NH; elution solvent:heptane-ethyl acetate system) to obtain 33 mg of the racemic titlecompound. The property values of the compound are as follows.

ESI-MS; m/z 416 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 3.10-3.26(m, 1H), 3.28-3.42 (m, 1H), 3.88 (s, 3H), 4.30-4.40 (m, 1H), 4.44-4.53(m, 1H), 6.92 (brs, 1H), 7.11 (d, J=16.0 Hz, 1H), 7.15-7.26 (m, 3H),7.39-7.48 (m, 3H), 7.54-7.59 (m, 2H), 7.64 (d, J=16.0 Hz, 1H), 7.70(brs, 1H).

The racemic title compound (33 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=8:2) to obtain the title optically active compoundwith a retention time of 32 minutes and negative optical rotation (10mg) and the title optically active compound with a retention time of 36minutes and positive optical rotation (10 mg).

Example 162 Synthesis of(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine

Synthesis of tert-butylN′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazinecarboxylate

HOBT (420 mg) and EDC (590 mg) were sequentially added to a solution of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (530mg), tert-butyl carbazate (271 mg) and IPEA (0.71 mL) in DMF (10 mL),and the reaction solution was stirred at room temperature for 15 hours.Ethyl acetate and saturated sodium bicarbonate water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The resulting solid wasrecrystallized from a mixed solution of ethyl acetate and ethanol toobtain 668 mg of the title compound. The property values of the compoundare as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.51 (s, 9H), 2.30 (s, 3H), 3.88 (s, 3H), 6.45(d, J=15.6 Hz, 1H), 6.76 (brs, 1H), 6.93 (s, 1H), 7.09 (brs, 1H), 7.11(brd, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H),7.73 (s, 1H), 8.80 (brs, 1H).

Synthesis of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acidhydrazide dihydrochloride

A solution of 4 N hydrochloric acid in ethyl acetate (3 mL) was added toa solution of tert-butylN′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazinecarboxylate(668 mg) in ethyl acetate (5 mL) and methanol (1 mL), and the reactionsolution was stirred at room temperature for two hours. The solidprecipitated in the reaction solution was collected by filtration andwashed with diethyl ether to obtain 658 mg of the title compound. Theproperty value of the compound is as follows.

ESI-MS; m/z 273 [M⁺+H].

Synthesis of(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}amine

TEA (1.25 mL) was added to a solution of(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acidhydrazide dihydrochloride (771 mg) in DMF (15 mL) at room temperature,and the reaction solution was stirred at room temperature for 10minutes. 4-Fluorophenyl isocyanate (0.26 mL) was added to the reactionsolution at room temperature, and the reaction solution was stirred atroom temperature for one hour. The reaction solution was added to coldwater. The generated solid was separated by filtration, washed withwater and diethyl ether and then dried at 60° C. for three hours.Phosphorus oxychloride (15 mL) was added to the resulting solid at roomtemperature, and the reaction solution was heated under reflux for threehours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the residue. The generated solid was separated byfiltration, washed with diethyl ether and then dried at 60° C. for onehour to obtain 820 mg of the title compound. The property value of thecompound is as follows.

ESI-MS; m/z 392 [M⁺+H].

Synthesis of(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine

Acetic acid (10 mL) and ammonium acetate (6.8 g) were added to(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}amine(692 mg), and the reaction solution was stirred at 150° C. for 12 hours.The reaction solution was left to cool to room temperature and thenconcentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the resulting residue, followed by extraction withchloroform. The insoluble matter generated during separation was addedto the resulting extract, and THF and ethanol were further added toprovide a mixed solution. The mixed solution was concentrated underreduced pressure and solidified with ethyl acetate and diethyl ether toobtain 372 mg of the title compound. The property values of the compoundare as follows.

ESI-MS; m/z 391 [M⁺+H]. ¹H-NMR (DMSO-d₆) δ (ppm): 2.16 (s, 3H), 3.91 (s,3H), 7.04-7.19 (m, 4H), 7.27-7.30 (m, 1H), 7.36-7.48 (m, 2H), 7.51 (s,1H), 7.57-7.64 (m, 2H), 7.80 (s, 1H).

Example 163 Synthesis of8-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrimidin-7-one

Synthesis ofN-(4-fluorophenyl)-N-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}acrylamide

TEA (0.07 mL) was added to a suspension of(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}aminesynthesized in Example 162 (100 mg) in methylene chloride (3 mL) and THF(2 mL) at room temperature. Acrylic acid chloride (0.03 mL) was added tothe reaction solution at 0° C., and the reaction solution was stirred atroom temperature for two hours. TEA (0.08 mL) and acrylic acid chloride(0.04 mL) were added to the reaction solution at room temperature, andthe reaction solution was stirred at room temperature for two hours.Further, DMF (0.5 mL), acetonitrile (0.5 mL), DMAP (2 mg), TEA (0.08 mL)and acrylic acid chloride (0.04 mL) were added and the reaction solutionwas stirred at room temperature for 12 hours. The reaction solution wasconcentrated under reduced pressure. Ethyl acetate and a saturatedsodium bicarbonate solution were added to the residue, and the organiclayer was separated. The resulting organic layer was dried overmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system, then ethyl acetate-methanolsystem) to obtain 22 mg of the title compound. The property value of thecompound is as follows.

ESI-MS; m/z 446 [M⁺+H].

Synthesis of8-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrimidin-7-one

Acetic acid (1 mL) and ammonium acetate (0.11 g) were added toN-(4-fluorophenyl)-N-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}acrylamide(22 mg), and the reaction solution was stirred at 150° C. for six hours.The reaction solution was left to cool to room temperature and thenconcentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the resulting residue, followed by extraction withchloroform. The resulting extract was dried over magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system, then ethyl acetate-methanolsystem) to obtain 1 mg of the title compound. The property values of thecompound are as follows.

ESI-MS; m/z 445 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 3.16 (t,J=6.8 Hz, 2H), 3.91 (s, 3H), 4.39 (t, J=6.8 Hz, 2H), 6.85 (d, J=16.0 Hz,1H), 6.94 (s, 1H), 7.12-7.29 (m, 5H), 7.33-7.40 (m, 2H), 7.59 (d, J=16.0Hz, 1H), 7.73 (d, J=1.2 Hz, 1H).

Example 164 Synthesis of4-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6,7-dihydro-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one

DMF (3 mL) and TEA (0.06 mL) were added to(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}aminesynthesized in Example 162 (44 mg), and the reaction solution wasstirred at room temperature for 10 minutes. Acrylic acid chloride (0.01mL) was added to the reaction solution at room temperature, and thereaction solution was stirred at room temperature for one hour and at60° C. for two hours. TEA (0.03 mL) and acrylic acid chloride (0.01 mL)were added to the reaction solution at 60° C., and the reaction solutionwas stirred at 60° C. for four hours. The reaction solution was left tocool to room temperature and then diluted with ethyl acetate and washedwith a saturated sodium bicarbonate solution and a saturated sodiumchloride solution. The resulting organic layer was dried over magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (carrier: Chromatorex NH;elution solvent: heptane-ethyl acetate system, then ethylacetate-methanol system) and further purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system, thenethyl acetate-methanol system) to obtain 6 mg of the title compound. Theproperty values of the compound are as follows.

ESI-MS; m/z 445 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=0.8 Hz, 3H),3.23 (t, J=7.2 Hz, 2H), 3.86 (s, 3H), 4.47 (t, J=7.2 Hz, 2H), 6.90-6.92(m, 1H), 6.94 (d, J=16.0 Hz, 1H), 7.11-7.15 (m, 2H), 7.19-7.27 (m, 3H),7.33-7.38 (m, 2H), 7.46 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).

Example 165 Synthesis of8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-4H-1,3,3a,8-tetraazaazulene

60% sodium hydride (10 mg) was added to a solution of(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}aminesynthesized in Example 162 (47.5 mg) in DMF (3 mL) at room temperature,and the reaction solution was stirred at room temperature for 10minutes. 1,4-Dibromobutane (0.02 mL) was added to the reaction solutionat room temperature, and the reaction solution was stirred at roomtemperature for two hours. 60% sodium hydride (5 mg) was added to thereaction solution at room temperature, and the reaction solution wasstirred at room temperature for two hours. A saturated ammonium chloridesolution was added to the reaction solution at 0° C., followed byextraction with ethyl acetate. The resulting extract was washed with asaturated sodium bicarbonate solution and a saturated sodium chloridesolution. The resulting organic layer was dried over magnesium sulfateand then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system, then ethyl acetate-methanolsystem), silica gel column chromatography (elution solvent:heptane-ethyl acetate system, then ethyl acetate-methanol system) andCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: ethanol) to obtain 14 mg of the title compound. Theproperty values of the compound are as follows.

ESI-MS; m/z 445 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.94-2.06 (m, 4H), 2.29(s, 3H), 3.69-3.76 (m, 2H), 3.85 (s, 3H), 4.23-4.30 (m, 2H), 6.89-6.95(m, 2H), 7.00-7.06 (m, 2H), 7.10-7.22 (m, 5H), 7.40 (d, J=16.0 Hz, 1H),7.68 (d, J=0.8 Hz, 1H).

Examples 166 and 167 Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 5-hydroxy-3-phenylpentanoic acid hydrazide

Hydrazine monohydrate (1.6 mL) was added to a solution of4-phenyl-tetrahydropyran-2-one (573 mg; CAS No. 61949-75-5) in ethanol(3 mL) at room temperature, and the reaction solution was heated underreflux for three hours. The reaction solution was left to cool to roomtemperature and then concentrated under reduced pressure. A saturatedsodium bicarbonate solution was added to the resulting residue, followedby extraction with chloroform. The resulting extract was dried overmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: ethyl acetate-methanol system) to obtain 492 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 209 [M⁺+H].

Synthesis of and2-(4-chloro-2-phenylbutyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole

IPEA (2.0 mL),(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (600mg) and BOPCl (0.71 g) were added to a solution of5-hydroxy-3-phenylpentanoic acid hydrazide (492 mg) in methylenechloride (20 mL) at room temperature, and the reaction solution wasstirred at room temperature for seven hours. Water was added to thereaction solution, followed by extraction with chloroform. The resultingextract was washed with a saturated sodium bicarbonate solution. Theresulting organic layer was dried over magnesium sulfate and thenconcentrated under reduced pressure. Phosphorus oxychloride (10 mL) wasadded to the resulting residue at room temperature, and the reactionsolution was heated under reflux for 1.5 hours. The reaction solutionwas left to cool to room temperature and then concentrated under reducedpressure. A saturated sodium bicarbonate solution was added to theresidue, followed by extraction with ethyl acetate. The resultingextract was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex NH; elution solvent: heptane-ethylacetate system) to obtain 445 mg of the title compound. The propertyvalue of the compound is as follows.

ESI-MS; m/z 449 [M⁺+H].

Synthesis of(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Acetic acid (5 mL) and ammonium acetate (1.2 g) were added to2-(4-chloro-2-phenylbutyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole(224 mg), and the reaction solution was stirred at 150° C. for 17 hours.The reaction solution was left to cool to room temperature and thenconcentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the resulting residue, followed by extraction withethyl acetate. The resulting extract was dried over magnesium sulfateand then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system) to obtain 115 mg of the racemictitle compound. The property values of the compound are as follows.

ESI-MS; m/z 412 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.27-2.44 (m, 2H), 2.30(d, J=0.8 Hz, 3H), 3.00-3.11 (m, 1H), 3.25-3.37 (m, 2H), 3.88 (s, 3H),4.17-4.26 (m, 1H), 4.27-4.35 (m, 1H), 6.91-6.94 (m, 1H), 7.08 (d, J=16.4Hz, 1H), 7.15-7.32 (m, 6H), 7.35-7.40 (m, 2H), 7.55 (d, J=16.4 Hz, 1H),7.70 (d, J=1.6 Hz, 1H).

The racemic title compound (26 mg) was separated by CHIRALPAK™ IAmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:IPA=1:4) to obtain the title optically active compoundwith a retention time of 25 minutes and negative optical rotation (10mg) and the title optically active compound with a retention time of 29minutes and positive optical rotation (6.6 mg).

Examples 168 and 169 Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 6-chloro-2-methoxy-3-nitropyridine

Sodium methoxide (2.8 g) was added to a solution of2,6-dichloro-3-nitropyridine (10 g) in THF (100 mL) at 0° C., and thereaction solution was stirred at room temperature for 13 hours. Asaturated ammonium chloride solution and ethyl acetate were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 6.49 g of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 189 [M⁺+H].

Synthesis of ethyl (E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylate

Palladium acetate (386 mg), 2-(di-tert-butylphosphino)biphenyl (1.03 g),triethylamine (9.59 mL) and ethyl acrylate (18.6 mL) were added to asolution of 6-chloro-2-methoxy-3-nitropyridine (6.49 g) in DMF (100 mL).The reaction solution was stirred in a nitrogen atmosphere at 120° C.for two hours and then left to cool to room temperature. The reactionsolution was concentrated under reduced pressure. Water and ethylacetate were added to the resulting residue, and the organic layer wasseparated. The resulting organic layer was washed with water and brine,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) and crystallized fromheptane to obtain 2.1 g of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.37 (t, J=7.6 Hz, 3H), 4.15 (s, 3H), 4.30 (q,J=7.6 Hz, 2H), 7.00 (d, J=16.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.56 (d,J=16.0 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H).

Synthesis of ethyl (E)-3-(5-amino-6-methoxypyridin-2-yl)acrylate

Iron (3.72 g) and ammonium chloride (7.13 g) were added to a solution ofethyl (E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylate (2.1 g) in ethanol(100 mL) and water (20 mL). The reaction solution was stirred at 100° C.for one hour and then left to cool to room temperature. The reactionsolution was filtered through celite. Ethyl acetate was added and theorganic layer was separated. The resulting organic layer was washed withsaturated sodium bicarbonate water and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system) to obtain 1.85 g of the titlecompound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.33 (t, J=7.2 Hz, 3H), 4.01 (s, 3H), 4.07 (brs,2H), 4.25 (q, J=7.2 Hz, 2H), 6.71 (d, J=15.6 Hz, 1H), 6.78 (d, J=7.6 Hz,1H), 6.84 (d, J=7.6 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H).

Synthesis of ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate

A mixed solution prepared from acetic anhydride (6.29 mL) and formicacid (9.42 mL) was added dropwise to a solution of ethyl(E)-3-(5-amino-6-methoxypyridin-2-yl)acrylate (1.85 g) in THF (30 mL) at0° C. The reaction solution was stirred at room temperature for one hourand then added dropwise to ice water. Ethyl acetate was added and theorganic layer was separated. The resulting organic layer was washed withsaturated sodium bicarbonate water and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure.Subsequently, cesium carbonate (4.87 g), potassium iodide (124 mg) andchloroacetone (1.23 mL) were added to a solution of the residue in DMF(20 mL), and the reaction solution was stirred at room temperature for12 hours. Ice water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain a crude product. Subsequently,ammonium acetate (2.88 g) was added to a solution of the resultingcompound in acetic acid (4.28 mL), and the reaction solution was stirredat 130° C. for one hour. The reaction solution was left to cool to roomtemperature. Ice water and ethyl acetate were added and the organiclayer was separated. The resulting organic layer was washed withsaturated sodium bicarbonate water and brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system) to obtain 1.50 g of the titlecompound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.36 (t, J=7.2 Hz, 3H), 2.30 (d, J=0.8 Hz, 3H),4.07 (s, 3H), 4.29 (q, J=7.2 Hz, 2H), 6.95 (d, J=15.6 Hz, 1H), 6.80 (d,J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H), 7.83 (d,J=0.8 Hz, 1H).

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid

A 5 N sodium hydroxide solution (4 mL) was added to a solution of ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate (1.5g) in methanol (10 mL) and THF (6 mL). The reaction solution was stirredat room temperature for two hours, and then 5 N hydrochloric acid (5 mL)was added to the reaction solution. The generated precipitate wasfiltered and washed with THF to obtain 755 mg of the title compound. Theproperty values of the compound are as follows.

ESI-MS; m/z 260 [M⁺+H]. ¹H-NMR (DMSO-d₆) δ (ppm): 2.16 (s, 3H), 3.99 (s,3H), 6.81 (d, J=16.0 Hz, 1H), 7.27 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.57(d, J=16.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.94 (s, 1H).

Synthesis of 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one

6.6 g of the title compound was obtained from3,4,5-trifluorophenylacetic acid (11 g) according to the method inExamples 20 and 21. The property value of the compound is as follows.

ESI-MS; m/z 245 [M⁺+H].

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]acrylamide

EDC (667 mg), HOBT (470 mg) and IPEA (1.01 mL) were added to asuspension of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(300 mg) and 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one (368 mg)in DMF (10 mL). The reaction solution was stirred at room temperaturefor 15 hours. Then, water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The resulting organiclayer was washed with brine, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: ethylacetate-methanol system) to obtain 508 mg of the title compound. Theproperty value of the compound is as follows.

ESI-MS; m/z 486 [M⁺+H].

Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Phosphorus oxychloride (5 mL) was added to(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]acrylamide(508 mg). The reaction solution was stirred at 120° C. for one hour andthen concentrated under reduced pressure. Subsequently, ammonium acetate(2.43 g) was added to a solution of the residue in acetic acid (5 mL),and the reaction solution was stirred at 150° C. for two hours. Thereaction solution was left to cool to room temperature and thenconcentrated under reduced pressure. Saturated sodium bicarbonate waterand ethyl acetate were added to the resulting residue, and the organiclayer was separated. The resulting organic layer was washed with brine,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtaina racemate of the title compound. The resulting racemate was separatedby CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm; mobile phase: ethanol) to obtain the title optically activecompound with a retention time of 6 minutes and positive opticalrotation (108.8 mg, >99% ee) and the title optically active compoundwith a retention time of 8 minutes and negative optical rotation (104.8mg, >99% ee).

The property values of the title compound with a retention time of 6minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.99-2.06 (m, 1H),2.11-2.22 (m, 2H), 2.29 (d, J=1.2 Hz, 3H), 2.34-2.40 (m, 1H), 4.05 (s,3H), 4.25-4.31 (m, 3H), 4.39-4.45 (m, 1H), 6.81 (dd, J=8.0, 6.4 Hz, 2H),6.94 (d, J=8.0 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H),7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

The property values of the title compound with a retention time of 8minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.99-2.06 (m, 1H),2.11-2.22 (m, 2H), 2.29 (d, J=1.2 Hz, 3H), 2.34-2.40 (m, 1H), 4.05 (s,3H), 4.25-4.31 (m, 3H), 4.39-4.45 (m, 1H), 6.81 (dd, J=8.0, 6.4 Hz, 2H),6.94 (d, J=8.0 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H),7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

Examples 170 and 171 Synthesis of (+) and(−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

242 mg of the racemic title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(600 mg) and 1-amino-3-(3,4-difluorophenyl)piperidin-2-one (471 mg) inthe same manner as in Examples 168 and 169. The property values of thecompound are as follows.

ESI-MS; m/z 449 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.25 (m, 3H), 2.29 (s, 3H), 2.31-2.41 (m,1H), 4.05 (s, 3H), 4.27-4.32 (m, 3H), 6.87-6.91 (m, 1H), 6.93-6.95 (m,2H), 6.97-7.00 (m, 1H), 7.09-7.16 (m, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.46(d, J=7.2 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H).

The racemic title compound was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol)to obtain the title optically active compound with a retention time of13.5 minutes and positive optical rotation (100 mg) and the titleoptically active compound with a retention time of 20.0 minutes andnegative optical rotation (94 mg).

Examples 172 and 173 Synthesis of(+)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(4-fluorophenyl)piperidin-2-one

3.6 g of the title compound was obtained from 4-fluorophenylacetic acid(6 g) according to the method in Examples 20 and 21. The property valueof the compound is as follows.

ESI-MS; m/z 209 [M⁺+H].

Synthesis of(+)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(150 mg) and 1-amino-3-(4-fluorophenyl)piperidin-2-one (181 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) toobtain the title optically active compound with a retention time of 18minutes and positive optical rotation (6.2 mg, >99% ee) and the titleoptically active compound with a retention time of 42 minutes andnegative optical rotation (5.5 mg, >99% ee).

The property values of the title compound with a retention time of 18minutes are as follows.

ESI-MS; m/z 431 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.10 (m, 2H),2.16-2.22 (m, 1H), 2.29 (s, 3H), 2.33-2.38 (m, 1H), 4.04 (s, 3H),4.27-4.35 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m,2H), 7.08-7.12 (m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.64 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).

The property values of the title compound with a retention time of 42minutes are as follows.

ESI-MS; m/z 431 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.10 (m, 2H),2.16-2.22 (m, 1H), 2.29 (s, 3H), 2.33-2.38 (m, 1H), 4.04 (s, 3H),4.27-4.35 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m,2H), 7.08-7.12 (m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.64 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).

Examples 174 and 175 Synthesis of(−)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(3-chloro-4-fluorophenyl)piperidin-2-one

The title compound (2.8 g) was obtained from3-chloro-4-fluorophenylacetic acid (5.0 g) according to the method inExamples 20 and 21. The property value of the compound is as follows.

ESI-MS; m/z 243 [M⁺+H].

Synthesis of(−)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (30 mg) was obtained from1-amino-3-(3-chloro-4-fluorophenyl)piperidin-2-one (100 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(200 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ AD-H manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase: 80% ethanol-hexane,flow rate: 10 mL/min) to isolate the title optically active compoundwith a retention time of 19 minutes and positive optical rotation (13.6mg) and the title optically active compound with a retention time of 23minutes and negative optical rotation (13.6 mg). The property values ofthe title optically active compound with a retention time of 23 minutesare as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.96-2.26 (m, 3H), 2.26-2.44 (m, 1H), 2.29 (s,3H), 4.05 (s, 3H), 4.30 (t, J=6.0 Hz, 3H), 6.95 (d, J=8.0 Hz, 1H), 6.96(s, 1H), 7.00-7.06 (m, 1H), 7.12 (t, J=8.0 Hz, 1H), 7.20 (dd, J=2.4, 6.8Hz, 1H), 7.46 (d, J=16 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.65 (d, J=16Hz, 1H), 7.77 (d, J=1.6 Hz, 1H).

ESI-MS; m/z 465 [M⁺+H].

The property values of the title optically active compound with aretention time of 19 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 176 and 177 Synthesis of(−)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(4-chloro-3-fluorophenyl)piperidin-2-one

The title compound (940 mg) was obtained from4-chloro-3-fluorobenzaldehyde (5.0 g) according to the method inExamples 20 and 21. The property value of the compound is as follows.

ESI-MS; m/z 243 [M⁺+H].

Synthesis of(−)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (300 mg) was obtained from1-amino-3-(4-chloro-3-fluorophenyl)piperidin-2-one (200 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(477 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to isolate the title optically active compound with a retentiontime of 15 minutes and positive optical rotation (91 mg) and the titleoptically active compound with a retention time of 23 minutes andnegative optical rotation (82 mg). The property values of the titleoptically active compound with a retention time of 23 minutes are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.96-2.32 (m, 3H), 2.29 (s, 3H), 2.32-2.44 (m,1H), 4.05 (s, 3H), 4.24-4.36 (m, 3H), 6.88-7.00 (m, 4H), 7.37 (t, J=7.2Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.65 (d,J=15.6 Hz, 1H), 7.70 (s, 1H).

ESI-MS; m/z 465 [M⁺+H].

The property values of the title optically active compound with aretention time of 15 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 178 and 179 Synthesis of(−)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2,4,5-trifluorophenyl)piperidin-2-one

The title compound (2.4 g) was obtained from 2,4,5-trifluorophenylaceticacid (5.0 g) according to the method in Examples 20 and 21. The propertyvalue of the compound is as follows.

ESI-MS; m/z 245 [M⁺+H].

Synthesis of(−)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (19 mg) was obtained from1-amino-3-(2,4,5-trifluorophenyl)piperidin-2-one (200 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(439 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ AD-H manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase: 80% ethanol-hexane,flow rate: 10 mL/min) to isolate the title optically active compoundwith a retention time of 17 minutes and positive optical rotation (6.6mg) and the title optically active compound with a retention time of 26minutes and negative optical rotation (6.6 mg). The property values ofthe title optically active compound with a retention time of 26 minutesare as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.96-2.32 (m, 3H), 2.94 (s, 3H), 2.32-2.46 (m,1H), 4.05 (s, 3H), 4.26-4.38 (m, 2H), 4.50-4.56 (m, 1H), 6.78-6.88 (m,1H), 6.92-7.02 (m, 3H), 7.45 (d, J=16 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H),7.65 (d, J=16 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

ESI-MS; m/z 467 [M⁺+H].

The property values of the title optically active compound with aretention time of 17 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 180 and 181 Synthesis of(−)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2,3,6-trifluorophenyl)piperidin-2-one

The title compound (820 mg) was obtained from2,3,6-trifluorophenylacetic acid (2.0 g) according to the method inExamples 20 and 21. The property value of the compound is as follows.

ESI-MS; m/z 245 [M⁺+H].

Synthesis of(−)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (120 mg) was obtained from1-amino-3-(2,3,6-trifluorophenyl)piperidin-2-one (200 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(439 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to isolate the title optically active compound with a retentiontime of 11 minutes and positive optical rotation (54 mg) and the titleoptically active compound with a retention time of 16 minutes andnegative optical rotation (55 mg). The property values of the titleoptically active compound with a retention time of 16 minutes are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.44 (m, 4H), 2.29 (s, 3H), 4.04 (s, 3H),4.20-4.32 (m, 1H), 4.32-4.44 (m, 1H), 4.60-4.70 (m, 1H), 6.80-6.90 (m,1H), 6.93 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 7.04-7.16 (m, 1H), 7.41 (d,J=15.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.76(s, 1H).

ESI-MS; m/z 467 [M⁺+H].

The property values of the title optically active compound with aretention time of 11 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 182 and 183 Synthesis of(−)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2,5-difluorophenyl)piperidin-2-one

The title compound (790 mg) was obtained from 2,5-difluorophenylaceticacid (930 mg) according to the method in Examples 20 and 21. Theproperty value of the compound is as follows.

ESI-MS; m/z 227 [M⁺+H].

Synthesis of(−)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (170 mg) was obtained from1-amino-3-(2,5-difluorophenyl)piperidin-2-one (200 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(477 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to obtain the title optically active compound with a retentiontime of 11 minutes and positive optical rotation (48 mg) and the titleoptically active compound with a retention time of 22 minutes andnegative optical rotation (51 mg). The property values of the titleoptically active compound with a retention time of 22 minutes are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.32 (m, 3H), 2.29 (s, 3H), 2.32-2.46 (m,1H), 4.05 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.57 (t, J=5.6 Hz, 1H),6.64-6.73 (m, 1H), 6.90-7.00 (m, 3H), 7.00-7.10 (m, 1H), 7.46 (d, J=16Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.66 (d, J=16 Hz, 1H), 7.77 (s, 1H).

ESI-MS; m/z 449 [M⁺+H].

The property values of the title optically active compound with aretention time of 11 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 184 and 185 Synthesis of (+) and(−)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one The titlecompound (2.6 g) was obtained using 2-bromo-4-fluorophenylacetic acid (3g) as a starting material according to the method in Examples 20 and 21.The property value of the compound is as follows.

ESI-MS; m/z 289 [M⁺+H].

Synthesis of (+) and(−)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (149 mg) was obtained using1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one (300 mg) as a startingmaterial according to the method in Examples 168 and 169. The resultingracemate (149 mg) was separated by CHIRALPAK™ OD-H manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol,flow rate: 10 mL/min) to obtain the title optically active compound witha retention time of 23 minutes and positive optical rotation (44 mg) andthe title optically active compound with a retention time of 31 minutesand negative optical rotation (45 mg).

The property values of the title optically active compound with aretention time of 23 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.20 (m, 3H), 2.29 (s, 3H), 2.35-2.45 (m,1H), 4.05 (s, 3H), 4.29-4.32 (m, 2H), 4.72 (dd, J=6.8, 6.8 Hz, 1H),6.84-7.00 (m, 4H), 7.36 (dd, J=8.0, 2.8 Hz, 1H), 7.46 (d, J=16.0 Hz,1H), 7.47 (d, J=4.8 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz,1H).

The property values of the title optically active compound with aretention time of 31 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.20 (m, 3H), 2.29 (s, 3H), 2.35-2.45 (m,1H), 4.05 (s, 3H), 4.29-4.32 (m, 2H), 4.72 (dd, J=6.8, 6.8 Hz, 1H),6.84-7.00 (m, 4H), 7.36 (dd, J=8.0, 2.8 Hz, 1H), 7.46 (d, J=16.0 Hz,1H), 7.47 (d, J=4.8 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz,1H).

Examples 186 and 187 Synthesis of(+)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-chloro-4-fluorophenyl)piperidin-2-one

2.9 g of the title compound was obtained using methyl2-chloro-4-fluorophenylacetate (3 g) as a starting material according tothe method in Examples 20 and 21. The property value of the compound isas follows.

ESI-MS; m/z 243 [M⁺+H].

Synthesis of(+)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (174 mg) was obtained using1-amino-3-(2-chloro-4-fluorophenyl)piperidin-2-one (300 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (174 mg) was separated by CHIRALPAK™ OD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: ethanol, flow rate: 10 mL/min) to obtain the title opticallyactive compound with a retention time of 22 minutes and positive opticalrotation (68 mg) and the title optically active compound with aretention time of 30 minutes and negative optical rotation (69 mg).

The property values of the title optically active compound with aretention time of 22 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.99-2.41 (m, 7H), 4.05 (s, 3H), 4.27-4.34 (m,2H), 4.72 (dd, J=6.0, 6.0 Hz, 1H), 6.85-6.95 (m, 4H), 7.18 (dd, J=8.6,2.8 Hz, 1H), 7.43-7.48 (m, 2H), 7.66 (d, J=16 Hz, 1H), 7.70 (s, 1H).

The property values of the title optically active compound with aretention time of 30 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.99-2.41 (m, 7H), 4.05 (s, 3H), 4.27-4.34 (m,2H), 4.72 (dd, J=6.0, 6.0 Hz, 1H), 6.85-6.95 (m, 4H), 7.18 (dd, J=8.6,2.8 Hz, 1H), 7.43-7.48 (m, 2H), 7.66 (d, J=16 Hz, 1H), 7.70 (s, 1H).

Examples 188 and 189 Synthesis of(−)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(3-fluorophenyl)piperidin-2-one

The title compound (3.0 g) was obtained from 3-fluorophenylacetic acid(5.0 g) according to the method in Examples 20 and 21. The propertyvalue of the compound is as follows.

ESI-MS; m/z 209 [M⁺+H].

Synthesis of(−)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (110 mg) was obtained from1-amino-3-(3-fluorophenyl)piperidin-2-one (200 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(439 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to obtain the title optically active compound with a retentiontime of 13 minutes and positive optical rotation (29 mg) and the titleoptically active compound with a retention time of 22 minutes andnegative optical rotation (29 mg). The property values of the titleoptically active compound with a retention time of 22 minutes are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.30 (m, 3H), 2.29 (s, 3H), 2.30-2.46 (m,1H), 4.05 (s, 3H), 4.20-4.40 (m, 3H), 6.85 (d, J=10.4 Hz, 1H), 6.90-7.02(m, 4H), 7.24-7.36 (m, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.47 (d, J=15.6 Hz,1H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).

ESI-MS; m/z 431 [M⁺+H].

The property values of the title optically active compound with aretention time of 13 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 190 and 191 Synthesis of(−)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(3-chlorophenyl)piperidin-2-one

The title compound (3.5 g) was obtained from 3-chlorophenylacetic acid(5.0 g) according to the method in Examples 20 and 21. The propertyvalue of the compound is as follows.

ESI-MS; m/z 225 [M⁺+H].

Synthesis of(−)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (160 mg) was obtained from1-amino-3-(3-chlorophenyl)piperidin-2-one (200 mg) and(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(477 mg) according to the method in Examples 168 and 169. The racematewas optically resolved by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10mL/min) to isolate the title optically active compound with a retentiontime of 14 minutes and positive optical rotation (68 mg) and the titleoptically active compound with a retention time of 24 minutes andnegative optical rotation (67 mg). The property values of the titleoptically active compound with a retention time of 24 minutes are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.23 (m, 3H), 2.29 (s, 3H), 2.30-2.46 (m,1H), 4.05 (s, 3H), 4.20-4.38 (m, 3H), 6.92-6.98 (m, 2H), 7.00-7.06 (m,1H), 7.14 (s, 1H), 7.22-7.32 (m, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.47 (d,J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).

ESI-MS; m/z 447 [M⁺+H].

The property values of the title optically active compound with aretention time of 14 minutes and positive optical rotation correspondedto the values of the (−)-isomer.

Examples 192 and 193 Synthesis of(+)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-pyridineand(−)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-chlorophenyl)piperidin-2-one

The title compound (831 mg) was obtained using 2-chlorophenylacetic acid(1 g) as a starting material according to the method in Examples 20 and21. The property value of the compound is as follows.

ESI-MS; m/z 225 [M⁺+H].

Synthesis of(+)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (192 mg) was obtained from1-amino-3-(2-chlorophenyl)piperidin-2-one (250 mg) according to themethod in Examples 168 and 169. The resulting racemate (192 mg) wasseparated by CHIRALPAK™ OJ-H manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=8:2, flow rate: 11mL/min) to obtain the title optically active compound with a retentiontime of 34 minutes and positive optical rotation (37 mg) and the titleoptically active compound with a retention time of 40 minutes andnegative optical rotation (31 mg).

The property values of the title optically active compound with aretention time of 34 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.41 (m, 7H), 4.04 (s, 3H), 4.25-4.34 (m,2H), 4.76-4.79 (m, 1H), 6.85-6.95 (m, 3H), 7.18-7.26 (m, 2H), 7.40-7.48(m, 3H), 7.66 (d, J=16 Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 40 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.41 (m, 7H), 4.04 (s, 3H), 4.25-4.34 (m,2H), 4.76-4.79 (m, 1H), 6.85-6.95 (m, 3H), 7.18-7.26 (m, 2H), 7.40-7.48(m, 3H), 7.66 (d, J=16 Hz, 1H), 7.76 (s, 1H).

Examples 194 and 195 Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one

Thionyl chloride (2.72 mL) was added to a solution of2-trifluoromethylphenylacetic acid (1.9 g) in methanol (38 mL), and thereaction solution was stirred at room temperature for three hours. Thereaction solution was concentrated under reduced pressure. The resultingresidue was diluted with DMF. Sodium hydride (containing 40% of mineraloil, 410 mg) was added under ice-cooling, and the reaction solution wasstirred for 10 minutes. The reaction solution was further stirred atroom temperature for 30 minutes and then ice-cooled again.1-Chloro-3-iodopropane (1.02 mL) was added to the reaction mixture, andthe reaction solution was stirred at room temperature overnight. Waterand ethyl acetate were added to the reaction mixture and the organiclayer was separated. The resulting organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The resultingresidue was diluted with ethanol (26.6 mL). Hydrazine monohydrate (7.6mL) was added, and the reaction solution was stirred at room temperaturefor two hours and then at 60° C. for further three hours. The reactionmixture was concentrated under reduced pressure. Saturated aqueoussodium bicarbonate and ethyl acetate and were added to the residue, andthe organic layer was separated. The resulting organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (carrier: Chromatorex NH;elution solvent: heptane-ethyl acetate system) to obtain 1.68 g of thetitle compound. The property values of the compound are as follows.

ESI-MS; m/z 259 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.82-2.10 (m, 3H),2.18-2.26 (m, 1H), 3.58-3.76 (m, 2H), 4.07 (dd, J=10.0, 5.6 Hz, 1H),4.60 (s, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.51 (t,J=7.6 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H).

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]acrylamide

EDC (834 mg), HOBT (588 mg) and IPEA (2.03 mL) were added to asuspension of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acidtrifluoroacetate (1.42 g) and1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (750 mg) in DMF (30mL). The reaction mixture was stirred at room temperature for 14 hours.Then, saturated aqueous sodium bicarbonate and ethyl acetate were addedto the reaction solution, and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: ethyl acetate-methanol system) to obtain 1.23 g of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 500 [M⁺+H].

Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Phosphorus oxychloride (24.2 mL) was added to(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]acrylamide(1.2 g). The reaction solution was stirred at 100° C. for one hour andthen concentrated under reduced pressure. Subsequently, the residue wasdiluted with acetic acid (24.2 mL). Then, ammonium acetate (1.9 g) wasadded and the reaction solution was stirred at 150° C. for two hours.The reaction solution was left to cool to room temperature and thenconcentrated under reduced pressure. Saturated aqueous sodiumbicarbonate and ethyl acetate were added to the resulting residue, andthe organic layer was separated. The resulting organic layer was driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system)to obtain a racemate of the title compound (750 mg). The resultingracemate (410 mg) was separated by CHIRALPAK™ IA manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase; hexane:ethanol=8:2,flow rate: 10 mL/min) to obtain the title optically active compound witha retention time of 28 minutes and positive optical rotation (174 mg),and the title optically active compound with a retention time of 33minutes and negative optical rotation (170 mg).

The property values of the title optically active compound with aretention time of 28 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (d,J=1.2 Hz, 3H), 2.42-2.51 (m, 1H), 4.03 (s, 3H), 4.28-4.41 (m, 2H), 4.70(dd, J=8.4, 6.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.95 (t, J=1.2 Hz, 1H),7.01 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H),7.45 (d, J=8.0 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H),7.72 (d, J=7.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 33 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (d,J=1.2 Hz, 3H), 2.42-2.51 (m, 1H), 4.03 (s, 3H), 4.28-4.41 (m, 2H), 4.70(dd, J=8.4, 6.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.95 (t, J=1.2 Hz, 1H),7.01 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H),7.45 (d, J=8.0 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H),7.72 (d, J=7.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

Examples 196 and 197 Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-6-(4-trifluoromethyl-phenyl)-piperidin-2-one

1.0 g of the title compound was obtained using4-(trifluoromethyl)phenylacetic acid as a starting material according tothe method in Examples 20 and 21. The property value of the compound isas follows.

ESI-MS; m/z 259 [M⁺+H].

Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (13.2 mg) was obtained using1-amino-6-(4-trifluoromethyl-phenyl)-piperidin-2-one (203 mg) as astarting material according to the method in Examples 168 and 169. Here,the compounds of Examples 200 and 201 described below (149 mg) weregenerated at the same time. The resulting racemate (13.2 mg) wasseparated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 12 mL/min) to obtainthe title optically active compound with a retention time of 10 minutesand positive optical rotation (2.8 mg) and the title optically activecompound with a retention time of 15 minutes and negative opticalrotation (3.0 mg).

The property values of the title optically active compound with aretention time of 10 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.26 (m, 3H), 2.30 (s, 3H), 2.36-2.48 (m,1H), 4.05 (s, 3H), 4.28-4.36 (m, 2H), 4.41 (t, J=7.3 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 6.95-6.97 (m, 1H), 7.26-7.30 (m, 2H), 7.45 (d, J=8.1 Hz,1H), 7.46 (d, J=16.1 Hz, 1H), 7.59-7.63 (m, 2H), 7.65 (d, J=16.1 Hz,1H), 7.77 (d, J=1.5 Hz, 1H).

The property values of the title optically active compound with aretention time of 15 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.26 (m, 3H), 2.30 (s, 3H), 2.36-2.48 (m,1H), 4.05 (s, 3H), 4.28-4.36 (m, 2H), 4.41 (t, J=7.3 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 6.95-6.97 (m, 1H), 7.26-7.30 (m, 2H), 7.45 (d, J=8.1 Hz,1H), 7.46 (d, J=16.1 Hz, 1H), 7.59-7.63 (m, 2H), 7.65 (d, J=16.1 Hz,1H), 7.77 (d, J=1.5 Hz, 1H).

Examples 198 and 199 Synthesis of(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(naphthalen-1-yl)piperidin-2-one

858 mg of the title compound was obtained using 1-naphthylacetic acid asa starting material according to the method in Examples 20 and 21. Theproperty value of the compound is as follows.

ESI-MS; m/z 241 [M⁺+H].

Synthesis of(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (173 mg) was obtained from1-amino-3-(naphthalen-1-yl)piperidin-2-one (254 mg) as a startingmaterial according to the method in Examples 168 and 169. The resultingracemate (173 mg) was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate:12 mL/min) to obtain the title optically active compound with aretention time of 11 minutes and negative optical rotation (74 mg) andthe title optically active compound with a retention time of 30 minutesand positive optical rotation (52 mg).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.02-2.32 (m, 3H), 2.29 (s, 3H), 2.40-2.50 (m,1H), 4.05 (s, 3H), 4.29 (ddd, J=13.2, 8.8, 5.9 Hz, 1H), 4.43 (ddd,J=13.2, 5.1, 5.1 Hz, 1H), 5.22 (t, J=5.5 Hz, 1H), 6.86 (d, J=7.3 Hz,1H), 6.92 (d, J=7.7 Hz, 1H), 6.94-6.97 (m, 1H), 7.35-7.40 (m, 1H), 7.45(d, J=7.7 Hz, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.50-7.60 (m, 2H), 7.69 (d,J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H),7.89-7.92 (m, 1H), 8.01 (d, J=8.4 Hz, 1H).

The property values of the title optically active compound with aretention time of 30 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.02-2.32 (m, 3H), 2.29 (s, 3H), 2.40-2.50 (m,1H), 4.05 (s, 3H), 4.29 (ddd, J=13.2, 8.8, 5.9 Hz, 1H), 4.43 (ddd,J=13.2, 5.1, 5.1 Hz, 1H), 5.22 (t, J=5.5 Hz, 1H), 6.86 (d, J=7.3 Hz,1H), 6.92 (d, J=7.7 Hz, 1H), 6.94-6.97 (m, 1H), 7.35-7.40 (m, 1H), 7.45(d, J=7.7 Hz, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.50-7.60 (m, 2H), 7.69 (d,J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H),7.89-7.92 (m, 1H), 8.01 (d, J=8.4 Hz, 1H).

Examples 200 and 201 Synthesis of(+)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-oland(−)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol

A racemate of the title compound (149 mg) was obtained from1-amino-6-(4-trifluoromethyl-phenyl)-piperidin-2-one (203 mg) accordingto the method in Examples 168 and 169. The resulting racemate (149 mg)was separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 12mL/min) to obtain the title optically active compound with a retentiontime of 19 minutes and positive optical rotation (39 mg) and the titleoptically active compound with a retention time of 39 minutes andnegative optical rotation (41 mg).

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.26 (m, 3H), 2.28 (s, 3H), 2.37-2.44 (m,1H), 4.30-4.37 (m, 2H), 4.40 (t, J=7.0 Hz, 1H), 6.35 (d, J=7.7 Hz, 1H),7.18 (d, J=16.5 Hz, 1H), 7.20 (3.6 Hz, 1H), 7.24-7.28 (m, 2H), 7.39 (d,J=16.5 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.62-7.56 (m, 2H), 8.18 (brd-s,1H).

The property values of the title optically active compound with aretention time of 39 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.26 (m, 3H), 2.28 (s, 3H), 2.37-2.44 (m,1H), 4.30-4.37 (m, 2H), 4.40 (t, J=7.0 Hz, 1H), 6.35 (d, J=7.7 Hz, 1H),7.18 (d, J=16.5 Hz, 1H), 7.20 (3.6 Hz, 1H), 7.24-7.28 (m, 2H), 7.39 (d,J=16.5 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.62-7.56 (m, 2H), 8.18 (brd-s,1H).

Examples 202 and 203 Synthesis of(+)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-oland(−)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol

A racemate of the title compound (30 mg) was obtained from1-amino-6-(4-fluorophenyl)-piperidin-2-one (500 mg) according to themethod in Examples 168 and 169. The resulting racemate (30 mg) wasseparated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtainthe title optically active compound with a retention time of 41 minutesand positive optical rotation (8.2 mg) and the title optically activecompound with a retention time of 51 minutes and negative opticalrotation (8.2 mg).

The property values of the title optically active compound with aretention time of 51 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.44 (m, 4H), 2.28 (s, 3H), 4.26-4.38 (m,3H), 6.35 (d, J=7.6 Hz, 1H), 6.98-7.07 (m, 2H), 7.07-7.14 (m, 2H),7.16-7.22 (m, 2H), 7.24-7.38 (m, 1H), 7.39 (d, J=7.6 Hz, 1H), 8.14 (d,J=1.6 Hz, 1H).

The property values of the title optically active compound with aretention time of 41 minutes corresponded to those of the titleoptically active compound with a retention time of 51 minutes.

Examples 204 and 205 Synthesis of(+)-2-{(E)-2-[6-ethoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-ethoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Cesium carbonate (22.6 mg) and methyl iodide (6.5 μl) were added toracemic3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol(26.9 mg) as a starting material in DMF (0.6 ml), and the reactionsolution was stirred at room temperature for four hours. Water and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The organic layer was washed with brine. The resultingorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 13.6 mg of a racemate of the title compound. Theresulting racemate (13.6 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol,flow rate: 12 mL/min) to obtain the title optically active compound witha retention time of 11 minutes and positive optical rotation (35 mg) andthe title optically active compound with a retention time of 16 minutesand negative optical rotation (41 mg).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.41 (t, J=7.3 Hz, 3H), 2.00-2.26 (m, 3H), 2.29(s, 3H), 2.36-2.45 (m, 1H), 4.29-4.34 (m, 2H), 4.42 (t, J=7.0 Hz, 1H),4.57 (q, J=7.3 Hz, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.95-6.98 (m, 1H),7.25-7.31 (m, 2H), 7.45 (d, J=15.7 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H),7.58-7.63 (m, 2H), 7.62 (d, J=15.7 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.41 (t, J=7.3 Hz, 3H), 2.00-2.26 (m, 3H), 2.29(s, 3H), 2.36-2.45 (m, 1H), 4.29-4.34 (m, 2H), 4.42 (t, J=7.0 Hz, 1H),4.57 (q, J=7.3 Hz, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.95-6.98 (m, 1H),7.25-7.31 (m, 2H), 7.45 (d, J=15.7 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H),7.58-7.63 (m, 2H), 7.62 (d, J=15.7 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H).

Examples 206 and 207 Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(150 mg) and 1-amino-3-phenylpiperidin-2-one (120 mg) according to themethod in Examples 168 and 169. The resulting racemate was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=1:1) to obtain the title opticallyactive compound with a retention time of 18 minutes and positive opticalrotation (45.1 mg, >99% ee) and the title optically active compound witha retention time of 42 minutes and negative optical rotation (46.5mg, >99% ee).

The property values of the title compound with a retention time of 18minutes are as follows.

ESI-MS; m/z 413 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.10 (m, 2H),2.16-2.21 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.33-2.38 (m, 1H), 4.04 (s,3H), 4.26-4.38 (m, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 7.11-7.13(m, 2H), 7.26-7.35 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz,1H), 7.65 (d, J=16.0 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H).

The property values of the title compound with a retention time of 42minutes are as follows.

ESI-MS; m/z 413 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.10 (m, 2H),2.16-2.21 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.33-2.38 (m, 1H), 4.04 (s,3H), 4.26-4.38 (m, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 7.11-7.13(m, 2H), 7.26-7.35 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz,1H), 7.65 (d, J=16.0 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H).

Examples 208 and 209 Synthesis of(+)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(4-chlorophenyl)piperidin-2-one

1.69 g of the title compound was obtained from methyl4-chlorophenylacetate (5 g) according to the method in Examples 20 and21. The property value of the compound is as follows.

ESI-MS; m/z 225 [M⁺+H].

Synthesis of(+)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(150 mg) and 1-amino-3-(4-chlorophenyl)piperidin-2-one (143 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=8:2) toobtain the title optically active compound with a retention time of 20minutes and positive optical rotation (45.3 mg, >99% ee) and the titleoptically active compound with a retention time of 24 minutes andnegative optical rotation (45.9 mg, >99% ee).

The property values of the title compound with a retention time of 20minutes are as follows.

ESI-MS; m/z 447 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.12 (m, 2H),2.16-2.19 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.31-2.41 (m, 1H), 4.04 (s,3H), 4.27-4.34 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H),7.05-7.09 (m, 2H), 7.28-7.32 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.45 (d,J=15.6 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

The property values of the title compound with a retention time of 24minutes are as follows.

ESI-MS; m/z 447 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.12 (m, 2H),2.16-2.19 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.31-2.41 (m, 1H), 4.04 (s,3H), 4.27-4.34 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H),7.05-7.09 (m, 2H), 7.28-7.32 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.45 (d,J=15.6 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

Examples 210 and 211 Synthesis of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-phenylpiperidin-2-one

2.83 g of the title compound was obtained from methyl phenylacetate (5g) according to the method in Examples 20 and 21. The property value ofthe compound is as follows.

ESI-MS; m/z 191 [M⁺+H].

Synthesis of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(CAS No. 870837-77-7, 300 mg) and 1-amino-3-phenylpiperidin-2-one (110mg) according to the method in Examples 168 and 169. The resultingracemate was separated by CHIRALPAK™ AD-H manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtainthe title optically active compound with a retention time of 5 minutesand negative optical rotation (33.8 mg, >99% ee) and the title opticallyactive compound with a retention time of 8 minutes and positive opticalrotation (34.5 mg, >99% ee).

The property values of the title compound with a retention time of 5minutes are as follows.

ESI-MS; m/z 413 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.11 (m, 2H),2.16-2.24 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.34-2.40 (m, 1H), 3.97 (s,3H), 4.25-4.37 (m, 3H), 7.10 (d, J=16.4 Hz, 1H), 7.12 (s, 1H), 7.13 (d,J=8.0 Hz, 1H), 7.26-7.37 (m, 3H), 7.46 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.52 (d, J=16.4 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2Hz, 1H).

The property values of the title compound with a retention time of 8minutes are as follows.

ESI-MS; m/z 413 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.11 (m, 2H),2.16-2.24 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.34-2.40 (m, 1H), 3.97 (s,3H), 4.25-4.37 (m, 3H), 7.10 (d, J=16.4 Hz, 1H), 7.12 (s, 1H), 7.13 (d,J=8.0 Hz, 1H), 7.26-7.37 (m, 3H), 7.46 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.52 (d, J=16.4 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2Hz, 1H).

Examples 212 and 213 Synthesis of(+)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(300 mg) and 1-amino-3-(4-fluorophenyl)piperidin-2-one (133 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 5.6 minutes andnegative optical rotation (48.1 mg, >99% ee) and the title opticallyactive compound with a retention time of 8 minutes and positive opticalrotation (46.2 mg, >99% ee).

The property values of the title compound with a retention time of 5.6minutes are as follows.

ESI-MS; m/z 431 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.10 (m, 2H),2.16-2.22 (m, 1H), 2.29 (s, 3H), 2.33-2.38 (m, 1H), 4.04 (s, 3H),4.27-4.35 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m,2H), 7.08-7.12 (m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.64 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).

The property values of the title compound with a retention time of 8minutes are as follows.

ESI-MS; m/z 431 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.10 (m, 2H),2.16-2.22 (m, 1H), 2.29 (s, 3H), 2.33-2.38 (m, 1H), 4.04 (s, 3H),4.27-4.35 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m,2H), 7.08-7.12 (m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.64 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).

Examples 214 and 215 Synthesis of(+)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(300 mg) and 1-amino-3-(4-fluorophenyl)piperidin-2-one (143 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=65:35) toobtain the title optically active compound with a retention time of 26minutes and positive optical rotation (26.2 mg, >99% ee) and the titleoptically active compound with a retention time of 31 minutes andnegative optical rotation (20.7 mg, >99% ee).

The property values of the title compound with a retention time of 26minutes are as follows. ESI-MS; m/z 447 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm):2.02-2.13 (m, 2H), 2.17-2.22 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.33-2.38(m, 1H), 3.96 (s, 3H), 4.26-4.32 (m, 3H), 7.05-7.10 (m, 3H), 7.29-7.32(m, 2H), 7.46 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.49 (d, J=16.0Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.33 (d, J=1.2 Hz, 1H).

The property values of the title compound with a retention time of 31minutes are as follows.

ESI-MS; m/z 447 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.13 (m, 2H),2.17-2.22 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.33-2.38 (m, 1H), 3.96 (s,3H), 4.26-4.32 (m, 3H), 7.05-7.10 (m, 3H), 7.29-7.32 (m, 2H), 7.46 (d,J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.49 (d, J=16.0 Hz, 1H), 8.13 (d,J=1.2 Hz, 1H), 8.33 (d, J=1.2 Hz, 1H).

Examples 216 and 217 Synthesis of(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-pyridin-3-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-pyridin-3-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (28.5 mg) was obtained using1-amino-6-(4-trifluoromethylphenyl)-piperidin-2-one (203 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (28.5 mg) was separated by CHIRALPAK™ IA manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol,flow rate: 12 mL/min) to obtain the title optically active compound witha retention time of 13 minutes and positive optical rotation (12 mg) andthe title optically active compound with a retention time of 16 minutesand negative optical rotation (15 mg).

The property values of the title optically active compound with positiveoptical rotation are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.26 (m, 3H), 2.29 (s, 3H), 2.36-2.46 (m,1H), 3.96 (s, 3H), 4.27-4.34 (m, 2H), 4.38 (t, J=6.9 Hz, 1H), 7.04 (d,J=16.4 Hz, 1H), 7.25-7.30 (m, 2H), 7.45 (d, J=1.8 Hz, 1H), 7.48 (d,J=16.4 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.58-7.63 (m, 2H), 8.13 (d,J=1.8 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H).

The property values of the title optically active compound with negativeoptical rotation are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.26 (m, 3H), 2.29 (s, 3H), 2.36-2.46 (m,1H), 3.96 (s, 3H), 4.27-4.34 (m, 2H), 4.38 (t, J=6.9 Hz, 1H), 7.04 (d,J=16.4 Hz, 1H), 7.25-7.30 (m, 2H), 7.45 (d, J=1.8 Hz, 1H), 7.48 (d,J=16.4 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.58-7.63 (m, 2H), 8.13 (d,J=1.8 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H).

Examples 218 and 219 Synthesis of(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

601 mg of the racemic title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(1.25 g) and 1-amino-3-(3,4-difluorophenyl)piperidin-2-one (547 mg)according to the method in Examples 168 and 169. The property values ofthe compound are as follows.

ESI-MS; m/z 449 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.01-2.25 (m, 3H), 2.29 (s, 3H), 2.31-2.40 (m,1H), 3.96 (s, 3H), 4.26-4.31 (m, 3H), 6.87-6.91 (m, 1H), 6.95-7.00 (m,1H), 7.08 (d, J=16.4 Hz, 1H), 7.10-7.17 (m, 1H), 7.26-7.51 (m, 3H), 8.13(d, J=1.6 Hz, 1H), 8.33 (d, J=1.2 Hz, 1H).

The racemic title compound (60 mg) was separated by CHIRALPAK™ AD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain the title optically active compound with aretention time of 21.7 minutes and negative optical rotation (13.6 mg)and the title optically active compound with a retention time of 28.8minutes and positive optical rotation (14.8 mg).

Examples 220 and 221 Synthesis of(R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic aciddiisopropylamide

4-Methyl-1H-imidazole (680 mg), copper iodide (78.8 mg),trans-1,2-bis(methylamino)cyclohexane (0.265 mL) and potassium carbonate(2.52 g) were added to a solution of5-iodo-4-methoxypyridine-2-carboxylic acid diisopropylamide synthesizedaccording to the method in Organic Letters, 2002, vol. 4, p. 2385 (3 g)in DMF (10 mL). The reaction solution was stirred in a sealed tube at110° C. for 20 hours. The reaction solution was left to cool to roomtemperature, and ethyl acetate was added. The insoluble matter wasremoved by filtration through celite. The resulting organic layer waswashed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 881 mg of the title compound. The property value ofthe compound is as follows.

ESI-MS; m/z 317 [M⁺+H].

Synthesis of ethyl(E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate

DIBAL-H (1.39 mL; 1.02 M solution in hexane) was added dropwise to asolution of 4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylicacid diisopropylamide (150 mg) in THF (5 mL) at −78° C. The reactionsolution was stirred at −78° C. for 15 minutes, and then heated to roomtemperature and stirred for 45 minutes. A saturated ammonium chloridesolution and ethyl acetate were added to the reaction solution. Asaturated Rochelle salt solution was further added and the reactionsolution was vigorously stirred for one hour. The resulting organiclayer was washed with saturated sodium bicarbonate water and brine,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. Subsequently, ethyl diethylphosphonoacetate (0.142 mL)and lithium hydroxide (18.2 mg) were added to a solution of theresulting residue in THF (3 mL), and the reaction solution was stirredat room temperature for 12 hours. Water and ethyl acetate were added tothe reaction solution, and the organic layer was separated. Theresulting organic layer was washed with brine, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system) to obtain 53 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 288 [M⁺+H].

Synthesis of(R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A 5 N sodium hydroxide solution (0.5 mL) was added to a mixed solutionof ethyl(E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate (90mg) in THF (2 mL) and methanol (1 mL). The reaction solution was stirredat room temperature for two hours. Then, 5 N hydrochloric acid (0.5 mL)was added, and the reaction solution was concentrated under reducedpressure. Subsequently, 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one(115 mg), EDC (180 mg), HOBT (127 mg) and IPEA (0.327 mL) were added toa solution of the resulting residue in DMF (3 mL). The reaction solutionwas stirred at room temperature for 15 hours. Then, water and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: ethyl acetate-methanol system) to obtain a crudecoupled compound. Subsequently, phosphorous oxychloride (3 mL) was addedto the compound. The reaction solution was stirred at 120° C. for onehour and then concentrated under reduced pressure. Subsequently,ammonium acetate (727 mg) was added to a solution of the residue inacetic acid (2 mL), and the reaction solution was stirred at 150° C. fortwo hours. The reaction solution was left to cool to room temperatureand then concentrated under reduced pressure. Saturated sodiumbicarbonate water and ethyl acetate were added to the resulting residue,and the organic layer was separated. The resulting organic layer waswashed with brine, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain a racemate of the title compound. The resultingracemate was separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 7 minutes (5.7mg, >99% ee) and the title optically active compound with a retentiontime of 9 minutes (5.6 mg, >99% ee).

The property values of the title compound with a retention time of 7minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.97-2.22 (m, 1H),2.11-2.22 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.34-2.40 (m, 1H), 3.91 (s,3H), 4.24-4.30 (m, 3H), 6.82 (dd, J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 6.99(s, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.58 (d, J=16.0 Hz, 1H), 7.67 (d,J=1.2 Hz, 1H), 8.41 (s, 1H).

The property values of the title compound with a retention time of 9minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.97-2.22 (m, 1H),2.11-2.22 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.34-2.40 (m, 1H), 3.91 (s,3H), 4.24-4.30 (m, 3H), 6.82 (dd, J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 6.99(s, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.58 (d, J=16.0 Hz, 1H), 7.67 (d,J=1.2 Hz, 1H), 8.41 (s, 1H).

Examples 222 and 223 Synthesis of (+) and(−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-1-methylvinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of N-(6-chloro-2-methoxypyridin-3-yl)formamide

Iron (11.9 g) and ammonium chloride (22.7 g) were added to a solution of6-chloro-2-methoxy-3-nitropyridine (10.0 g, CAS: 40851-91-0) in ethanol(130 mL) and water (52 mL). The reaction solution was stirred at 80 to90° C. for one hour and 20 minutes and then left to cool to roomtemperature. The reaction solution was filtered through celite andwashed with ethanol. Then, the filtrate was concentrated under reducedpressure. The residue was diluted with ethyl acetate and water, and theorganic layer was separated. The resulting organic layer was washed withbrine, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was diluted with THF (26 mL). TheTHF solution was added dropwise to a mixed solution of formic acid (20.1mL) and acetic anhydride (20.1 mL) at room temperature. Then, thereaction solution was stirred for one hour. Ice water (120 mL) was addedto the reaction solution, and the precipitated crystals were collectedby filtration. The crystals were washed with water and then air-dried toobtain 5.85 g of the title compound. The property value of the compoundis as follows.

ESI-MS; m/z 187 [M⁺+H].

Synthesis of N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide

Cesium carbonate (20.5 g), potassium iodide (521 mg) and chloroacetone(5.0 mL) were added to a solution ofN-(6-chloro-2-methoxypyridin-3-yl)formamide (5.85 g) in DMF (34.3 mL),and the reaction solution was stirred at 100° C. for one hour. Ice waterand chloroform were added to the reaction solution, and the organiclayer was separated. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system) to obtain 4.71 g of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 243 [M⁺+H].

Synthesis of 6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine

A mixture of N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide(4.71 g), acetic acid (11.1 mL) and ammonium acetate (7.48 g) wasstirred at 130° C. for one hour. The reaction solution was left to coolto room temperature. Ice water, ethyl acetate and aqueous ammonia wereadded and the organic layer was separated. The organic layer was driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: heptane-ethyl acetate system) to obtain 2.42 g of thetitle compound. The property values of the compound are as follows.

ESI-MS; m/z 224 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 4.02 (s, 3H), 6.91 (brs, 1H), 6.99(d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.71 (brs, 1H).

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacrylicacid

A mixture of 6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine(400 mg), an allylpalladium chloride dimer (32.8 mg),tri-o-tolylphosphine (54.4 mg), sodium acetate (441 mg),dimethylacetamide (0.640 mL), tert-butyl methacrylate (0.724 mL) andtoluene (2 mL) was stirred in a nitrogen atmosphere at 120° C. for 3.5hours. The reaction solution was left to cool to room temperature. Then,a silica gel was added and the reaction solution was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain313 mg of tert-butyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacrylate.The ester was diluted with trifluoroacetic acid (2.48 mL) and methylenechloride (2.48 mL), and the reaction solution was stirred at roomtemperature for 3.5 hours. The reaction solution was concentrated underreduced pressure to obtain 260 mg of the title compound. The propertyvalue of the compound is as follows.

ESI-MS; m/z 274 [M⁺+H].

Synthesis of (+) and(−)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-1-methylvinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

74.6 mg of the racemic title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacrylicacid (260 mg) and 1-amino-3-(3,4-difluorophenyl)piperidin-2-one (172 mg)according to the method in Examples 168 and 169. The racemic titlecompound was separated by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol:hexane=1:1) toobtain the title optically active compound with a retention time of 7.4minutes and positive optical rotation (11.9 mg) and the title opticallyactive compound with a retention time of 9.8 minutes and negativeoptical rotation (12.2 mg).

The property values of the title optically active compound with negativeoptical rotation are as follows.

ESI-MS; m/z 463 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.21 (m, 3H), 2.30 (s, 3H), 2.30-2.37 (m,1H), 2.75 (s, 3H), 4.06 (s, 3H), 4.23-4.36 (m, 3H), 6.86-6.90 (m, 1H),6.94-7.02 (m, 3H), 7.10-7.17 (m, 1H), 7.47-7.49 (m, 2H), 7.79 (d, J=1.2Hz, 1H).

The property values of the title optically active compound with positiveoptical rotation corresponded to the property values of the titleoptically active compound with negative optical rotation.

Example 224 Synthesis of8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

10.1 mg of the racemic title compound was obtained according to themethod in Example 53 from(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Example 170 (20 mg). The property values of the compound areas follows.

ESI-MS; m/z 465 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.98-2.08 (m, 1H), 2.16(ddd, J=13.6, 10.0, 3.2 Hz, 1H), 2.29 (s, 3H), 2.35 (ddd, J=13.6, 8.0,2.4 Hz, 1H), 2.36-2.50 (m, 1H), 4.00 (s, 3H), 4.23-4.40 (m, 2H), 5.23(brs, 1H), 6.78 (d, J=5.2 Hz, 1H), 6.94 (s, 1H), 7.01-7.07 (m, 1H), 7.13(q, J=8.4 Hz, 1H) 7.25-7.32 (m, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.41 (d,J=5.2 Hz, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H).

Example 225 Synthesis of8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol

7.2 mg of the title compound was obtained according to the method inExample 53 from(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineobtained in Example 219 (10.2 mg). The property values of the compoundare as follows.

ESI-MS; m/z 465 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.97-2.08 (m, 1H), 2.16(ddd, J=13.6, 10.4, 3.2 Hz, 1H), 2.28 (s, 3H), 2.35 (ddd, J=13.6, 8.4,3.2 Hz, 1H), 2.34-2.48 (m, 1H), 3.92 (s, 3H), 4.21-4.37 (m, 2H), 4.80(brs, 1H), 6.98-7.04 (m, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.12 (q, J=8.4Hz, 1H) 7.20-7.28 (m, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.43 (d, J=16.0 Hz,1H), 7.48 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 8.30 (s, 1H).

Examples 226 and 227 Synthesis of (−) and(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

70.6 mg of the racemic title compound was obtained from8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(100 mg) in the same manner as in Example 65. The property values of thecompound are as follows.

ESI-MS; m/z 474 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.15-2.26 (m, 1H), 2.30 (s, 3H), 2.35-2.48 (m,2H), 2.68-2.76 (m, 1H), 4.07 (s, 3H), 4.29-4.45 (m, 2H), 6.97 (d, J=1.2Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 7.10-7.28 (m, 3H), 7.50 (d, J=7.6 Hz,1H), 7.52 (d, J=15.6 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2Hz, 1H).

The racemic title compound was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase:hexane:ethanol=7:3) to obtain the title optically active compound with aretention time of 12.8 minutes and negative optical rotation (18.5 mg)and the title optically active compound with a retention time of 16.8minutes and positive optical rotation (19.8 mg).

Examples 228 and 229 Synthesis of (+) and(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

308 mg of the racemic title compound was obtained from2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(255 mg) in the same manner as in Example 65. The property values of thecompound are as follows.

ESI-MS; m/z 492 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.22-2.29 (m, 1H), 2.29 (s, 3H), 2.36-2.50 (m,2H), 2.69-2.75 (m, 1H), 3.98 (s, 3H), 4.27-4.42 (m, 2H), 7.02-7.06 (m,2H), 7.07 (d, J=16.4 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.53 (s, 1H), 7.56(d, J=16.4 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.36 (s, 1H).

The racemic title compound (48 mg) was separated by CHIRALPAK™ IAmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain the title optically active compound with aretention time of 12.9 minutes and positive optical rotation (8.35 mg)and the title optically active compound with a retention time of 14.6minutes and negative optical rotation (9.62 mg).

Examples 230 and 231 Synthesis of (−) and(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

174 mg of the racemic title compound was obtained as a crude productfrom8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(100 mg) in the same manner as in Example 65. The crude product wasseparated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title opticallyactive compound with a retention time of 14.3 minutes and negativeoptical rotation (22.4 m) and the title optically active compound with aretention time of 18.2 minutes and positive optical rotation (9.26 mg).

The property values of the title optically active compound with negativeoptical rotation are as follows.

ESI-MS; m/z 474 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.18-2.28 (m, 1H), 2.30 (d, J=1.2 Hz, 3H),2.36-2.48 (m, 2H), 2.69-2.74 (m, 1H), 3.99 (s, 3H), 4.28-4.44 (m, 2H),7.08-7.25 (m, 4H), 7.48 (d, J=2.0 Hz, 1H), 7.55-7.59 (m, 2H), 8.18 (d,J=2.0 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with positiveoptical rotation corresponded to those of the title optically activecompound with negative optical rotation.

Example 232 Synthesis of4-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

Synthesis of 3-(4-chlorophenylamino)propan-1-ol

4-Chloroaniline (4.39 g) and lithium tetrafluoroborate (3.32 g) wereadded to a solution of oxetane (1.00 g) in acetonitrile (20 mL) at roomtemperature, and the reaction solution was stirred at room temperaturefor 52 hours. A saturated sodium bicarbonate solution was added to thereaction solution, followed by extraction with chloroform. The resultingextract was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain2.17 g of the title compound. The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.88 (tt, J=6.4, 6.0 Hz, 2H), 3.25 (t, J=6.4 Hz,2H), 3.81 (brt, J=6.0 Hz, 2H), 3.90 (brs, 1H), 6.52-6.56 (m, 2H),7.08-7.13 (m, 2H).

Synthesis of 1-amino-3-(4-chlorophenyl)tetrahydropyrimidin-2-one

Thionyl chloride (4.4 mL) was added to a solution of3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at roomtemperature, and the reaction solution was stirred at 60° C. for fivehours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. Ice and a saturated sodiumbicarbonate solution were added, followed by extraction with ethylacetate (200 mL). Heptane (100 mL) was added to the resulting extract toprepare a mixed solution. The solution was purified by silica gel columnchromatography (elution solvent: heptane:ethyl acetate=2:1) to obtain(4-chlorophenyl)-(3-chloropropyl)amine.(4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45 mL).Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL) were added at0° C., and the reaction solution was stirred at room temperature for 15hours. Water was added to the reaction solution, followed by extractionwith ethyl acetate. The resulting extract was dried over magnesiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain phenyl(4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g). Phenyl(4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g) was dissolved inethanol (60 mL). Hydrazine monohydrate (5.65 mL) was added at roomtemperature, and the reaction solution was heated under reflux for 17hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. A saturated sodium bicarbonatesolution was added, followed by extraction with chloroform. Theresulting extract was dried over magnesium sulfate and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system, thenethyl acetate-methanol system) to obtain 2.19 g of the title compound.The property values of the compound are as follows.

ESI-MS; m/z 226 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.15 (tt, J=6.4, 5.6 Hz,2H), 3.62 (t, J=6.4 Hz, 2H), 3.65 (t, J=5.6 Hz, 2H), 4.31 (brs, 2H),7.17-7.22 (m, 2H), 7.26-7.31 (m, 2H).

Synthesis of(E)-N-[3-(4-chlorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

IPEA (0.65 mL), 1-amino-3-(4-chlorophenyl)tetrahydropyrimidin-2-one (139mg), EDC (177 mg) and HOBT (125 mg) were added to a solution of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(300 mg) in DMF (6 mL) at room temperature. The reaction solution wasstirred at room temperature for 24 hours. The reaction solution wasdiluted with ethyl acetate and washed with a saturated sodiumbicarbonate solution and a saturated sodium chloride solution. Theresulting organic layer was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (carrier: Chromatorex NH; elution solvent:heptane-ethyl acetate system, then ethyl acetate-methanol system) toobtain 287 mg of the title compound. The property value of the compoundis as follows.

ESI-MS; m/z 467 [M⁺+H].

Synthesis of4-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

Phosphorus oxychloride (5 mL) was added to(E)-N-[3-(4-chlorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide(287 mg), and the reaction mixture was heated under reflux for one hour.The reaction solution was left to cool to room temperature and thenconcentrated under reduced pressure. Acetic acid (5 mL) and ammoniumacetate (2.4 g) were added to the resulting residue, and the reactionsolution was stirred at 150° C. for two hours. The reaction solution wasleft to cool to room temperature and then concentrated under reducedpressure. A saturated sodium bicarbonate solution was added to theresulting residue, followed by extraction with chloroform. The resultingextract was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex NH; elution solvent: heptane-ethylacetate system) and further solidified with a mixed solvent of ethylacetate, diethyl ether and heptane to obtain 117 mg of the titlecompound. The property values of the compound are as follows.

ESI-MS; m/z 448 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=1.2 Hz, 3H),2.35-2.42 (m, 2H), 3.84 (brt, J=5.6 Hz, 2H), 4.05 (s, 3H), 4.23 (t,J=6.0 Hz, 2H), 6.93-6.97 (m, 2H), 7.33-7.41 (m, 3H), 7.46 (d, J=7.6 Hz,1H), 7.49-7.55 (m, 3H), 7.76 (d, J=1.2 Hz, 1H).

Example 233 Synthesis of2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

120 mg of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-(2-oxo-3-phenyl-tetrahydropyrimidin-1-yl)acrylamide(259 mg) by the same method as in Example 232. The property values ofthe compound are as follows.

ESI-MS; m/z 414 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 2.34-2.41(m, 2H), 3.88 (brt, J=5.6 Hz, 2H), 4.05 (s, 3H), 4.24 (t, J=6.0 Hz, 2H),6.93-6.96 (m, 2H), 7.12-7.27 (m, 1H), 7.36-7.43 (m, 3H), 7.45 (d, J=7.6Hz, 1H), 7.51-7.57 (m, 3H), 7.75 (brs, 1H).

Example 234 Synthesis of2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

175 mg of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(3,4,5-trifluorophenyl)-tetrahydropyrimidin-1-yl]acrylamide(298 mg) by the same method as in Example 232. The property values ofthe compound are as follows.

ESI-MS; m/z 468 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.35-2.44(m, 2H), 3.81 (t, J=5.6 Hz, 2H), 4.06 (s, 3H), 4.24 (t, J=6.0 Hz, 2H),6.95-7.01 (m, 2H), 7.31-7.37 (m, 2H), 7.41 (d, J=16.0 Hz, 1H), 7.48 (d,J=7.6 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.77 (s, 1H).

Examples 235 and 236 Synthesis of(R)-4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidineand(S)-4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

178 mg of the racemic title compound was obtained from(E)-N-[3-(4-fluorophenyl)-4-methyl-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide(378 mg) by the same method as in Example 232. The racemic titlecompound (178 mg) was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1)to obtain the title optically active compound with a retention time of31 minutes (75 mg) and the title optically active compound with aretention time of 39 minutes (75 mg).

The property values of the title optically active compound with aretention time of 31 minutes are as follows (Example 235).

ESI-MS; m/z 446 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.29 (d, J=6.4 Hz, 3H),2.10-2.18 (m, 1H), 2.29 (d, J=0.8 Hz, 3H), 2.37-2.48 (m, 1H), 4.03 (s,3H), 4.08-4.17 (m, 1H), 4.19-4.32 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.94(brs, 1H), 7.07-7.13 (m, 2H), 7.33 (d, J=15.6 Hz, 1H), 7.39-7.44 (m,2H), 7.44 (d, J=7.6 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.75 (d, J=0.8 Hz,1H).

The property values of the title optically active compound with aretention time of 39 minutes are as follows (Example 236).

ESI-MS; m/z 446 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.29 (d, J=6.4 Hz, 3H),2.10-2.18 (m, 1H), 2.29 (d, J=0.8 Hz, 3H), 2.37-2.48 (m, 1H), 4.03 (s,3H), 4.08-4.17 (m, 1H), 4.19-4.32 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.94(brs, 1H), 7.07-7.13 (m, 2H), 7.33 (d, J=15.6 Hz, 1H), 7.39-7.44 (m,2H), 7.44 (d, J=7.6 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.75 (d, J=0.8 Hz,1H).

Example 237 Synthesis of2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

Synthesis of(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]-N-(2-oxo-3-phenyl-tetrahydropyrimidin-1-yl)acrylamide

1-Amino-3-phenyl-tetrahydropyrimidin-2-one synthesized by the samemethod as in Example 232 at room temperature (111 mg; ESI-MS; m/z 192[M⁺+H]), IPEA (0.41 mL), EDC (166 mg) and HOBT (117 mg) were added to asolution of(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(300 mg) in DMF (6 mL). The reaction solution was stirred at roomtemperature for 24 hours. The reaction solution was diluted with ethylacetate and washed with a saturated sodium bicarbonate solution and asaturated sodium chloride solution. The resulting organic layer wasdried over magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system,then ethyl acetate-methanol system) to obtain 250 mg of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 433 [M⁺+H].

Synthesis of2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

Phosphorus oxychloride (4 mL) was added to(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]-N-(2-oxo-3-phenyl-tetrahydropyrimidin-1-yl)acrylamide(250 mg), and the reaction solution was heated under reflux for onehour. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. Acetic acid (3 mL) andammonium acetate (2.3 g) were added to the resulting residue, and thereaction solution was stirred at 150° C. for two hours. The reactionsolution was left to cool to room temperature and then concentratedunder reduced pressure. A saturated sodium bicarbonate solution wasadded to the resulting residue, followed by extraction with chloroform.The resulting extract was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (carrier: Chromatorex NH; elution solvent:heptane-ethyl acetate system) and further solidified with a mixedsolvent of ethyl acetate, diethyl ether and heptane to obtain 123 mg ofthe title compound. The property values of the compound are as follows.

ESI-MS; m/z 414 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.35-2.42 (m, 2H), 3.88 (t, J=6.0 Hz, 2H), 3.97 (s, 3H), 4.24 (t, J=6.0Hz, 2H), 6.99 (d, J=16.0 Hz, 1H), 7.14-7.19 (m, 1H), 7.39-7.58 (m, 7H),8.15 (d, J=1.6 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).

Example 238 Synthesis of4-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

199 mg of the racemic title compound was obtained from(E)-N-[3-(4-chlorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylamide(270 mg) by the same method as in Example 237. The property values ofthe compound are as follows.

ESI-MS; m/z 448 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.35-2.42 (m, 2H), 3.85 (brt, J=5.6 Hz, 2H), 3.98 (s, 3H), 4.23 (t,J=6.4 Hz, 2H), 6.98 (d, J=16.4 Hz, 1H), 7.35-7.39 (m, 2H), 7.44 (d,J=16.4 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.49-7.54 (m, 3H), 8.16 (d,J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).

Example 239 Synthesis of2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

180 mg of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]-N-[2-oxo-3-(3,4,5-trifluorophenyl)-tetrahydropyrimidin-1-yl]acrylamide(280 mg) by the same method as in Example 237. The property values ofthe compound are as follows.

ESI-MS; m/z 468 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.37-2.43 (m, 2H), 3.82 (brt, J=5.6 Hz, 2H), 4.00 (s, 3H), 4.24 (t,J=6.0 Hz, 2H), 6.99 (d, J=16.4 Hz, 1H), 7.31-7.37 (m, 2H), 7.44-7.55 (m,3H), 8.20 (d, J=1.6 Hz, 1H), 8.35 (d, J=1.2 Hz, 1H).

Examples 240 and 241 Synthesis of(R)-4-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidineand(S)-4-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

245 mg of the racemic title compound was obtained from(E)-N-[3-(4-fluorophenyl)-4-methyl-2-oxo-tetrahydropyrimidin-1-yl]-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylamide(445 mg) by the same method as in Example 237. The racemic titlecompound (180 mg) was separated by CHIRALPAK™ AD-H manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase:hexane:ethanol=1:1) to obtain the title optically active compound with aretention time of 22 minutes (80 mg) and the title optically activecompound with a retention time of 28 minutes (70 mg).

The property values of the title optically active compound with aretention time of 22 minutes are as follows (Example 240).

ESI-MS; m/z 446 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.29 (d, J=6.8 Hz, 3H),2.11-2.19 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.38-2.48 (m, 1H), 3.96 (s,3H), 4.08-4.17 (m, 1H), 4.20-4.31 (m, 2H), 6.96 (d, J=16.4 Hz, 1H),7.08-7.15 (m, 2H), 7.35-7.46 (m, 4H), 7.51 (brs, 1H), 8.13 (d, J=2.0 Hz,1H), 8.33 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 28 minutes are as follows (Example 241).

ESI-MS; m/z 446 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.29 (d, J=6.8 Hz, 3H),2.11-2.19 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.38-2.48 (m, 1H), 3.96 (s,3H), 4.08-4.17 (m, 1H), 4.20-4.31 (m, 2H), 6.96 (d, J=16.4 Hz, 1H),7.08-7.15 (m, 2H), 7.35-7.46 (m, 4H), 7.51 (brs, 1H), 8.13 (d, J=2.0 Hz,1H), 8.33 (d, J=1.2 Hz, 1H).

The following compounds were obtained using(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid by thesame method as in Example 232 (Table 7).

TABLE 7

Example E₃ DATA: MS m/z Note 242

M⁺ + H: 413 (ESI) 243

M⁺ + H: 447 (ESI) 244

M⁺ + H: 467 (ESI) 245

M⁺ + H: 427 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 1:1, retention time 18 min) 246

M⁺ + H: 427 (ESI) Optically active compound (separation conditions IA,hexane:ethanol = 1:1, retention time 23 min) 247

M⁺ + H: 463 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 1:1, retention time 30 min) 248

M⁺ + H: 463 (ESI) Optically active compound (separation conditions IB,hexane:ethanol = 1:1, retention time 36 min) 249

M⁺ + H: 445 (ESI) Optically active compound (separation conditions IA,IPA, retention time 20 min) 250

M⁺ + H: 445 (ESI) Optically active compound (separation conditions IA,IPA, retention time 25 min) 251

M⁺ + H: 399 (ESI) 252

M⁺ + H: 419 (ESI)

Example 253 and 254 Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Synthesis of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid

A 2.66 M solution of butyl lithium in hexane (20 mL) was added to asolution of 3,4,5-trifluorophenylacetic acid (5.00 g) in THF (150 mL) ina nitrogen atmosphere at −78° C., and the reaction solution was stirredat −78° C. for 20 minutes. The reaction solution was further stirred at0° C. for one hour. Then, 1-bromo-2-chloroethane (2.2 mL) was added at0° C., and the reaction solution was stirred at room temperature for 14hours. Ethyl acetate and 1 N hydrochloric acid were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was washed with a saturated sodium chloride solution. Theresulting organic layer was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 4.54 g of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.13-2.22 (m, 1H), 2.45-2.54 (m, 1H), 3.36 (ddd,J=11.6, 8.4, 4.8 Hz, 1H), 3.58 (ddd, J=11.6, 6.4, 5.2 Hz, 1H), 3.89 (dd,J=7.6, 7.6 Hz, 1H), 6.94-7.02 (m, 2H).

Synthesis of tert-butylN′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate

oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a solution of4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g) in methylenechloride (30 mL) at 0° C., and the reaction solution was stirred at roomtemperature for one hour. The reaction solution was concentrated underreduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyricacid chloride. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyricacid chloride in THF (5 mL) was added to a solution of tert-butylcarboxylate (600 mg) and triethylamine (3.1 mL) in THF (20 mL) at 0° C.,and the reaction solution was stirred at room temperature for one hour.The reaction solution was added to a saturated sodium bicarbonatesolution, followed by extraction with ethyl acetate. The resultingextract was dried over magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain1.35 g of the title compound. The property value of the compound is asfollows.

ESI-MS; m/z 389 [M⁺+Na]

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

Isopropyl chloroformate (3.99 mL) was added dropwise to a solution of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(5.2 g) and N,N-diisopropylethylamine (7.44 mL) in DMF (52 mL) underice-cooling, and the reaction solution was stirred for 20 minutes.Aqueous ammonic (5.2 mL) was added to the reaction solution, and thereaction solution was stirred at room temperature for 30 minutes.Similarly, ethyl chloroformate (3.76 mL) was added dropwise to asolution of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(4.8 g) and N,N-diisopropylethylamine (6.87 mL) in DMF (48 mL) underice-cooling, and the reaction solution was stirred for 10 minutes. Then,aqueous ammonia (5.2 mL) was added to the reaction solution, and thereaction solution was stirred at room temperature for 30 minutes. Thereaction solutions were mixed and diluted with water and chloroform, andthen the organic layer was separated. The aqueous layer was extractedwith chloroform five times. The organic layers were combined, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform-2-propanol system) to obtain 3.54 g of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 259 [M⁺+H].

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrile

A mixture of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide(3.54 g) and phosphorus oxychloride (12 ml) was stirred at 90° C. forone hour. The reaction solution was concentrated under reduced pressureand then diluted with ice water, chloroform and aqueous ammonia, and theorganic layer was separated. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was diluted with ether and the precipitated crystals werecollected by filtration. The crystals were washed with ether and thenair-dried to obtain 2.27 g of the title compound. The property value ofthe compound is as follows.

ESI-MS; m/z 241 [M⁺+H].

(E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrileis also synthesized by the following synthesis method.

Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)formaldehyde

Acetic anhydride (203 ml) was added dropwise to formic acid (204 ml)under ice-cooling, and the reaction solution was stirred at the sametemperature for 25 minutes. 6-Bromo-2-methoxypyridine-3-amine powder(CAS No. 89466-18-2, 146 g) was put into the reaction mixture over 10minutes, and then the reaction solution was stirred at the sametemperature for 30 minutes. The water bath was removed. tert-Butylmethyl ether (300 ml) and n-heptane (500 ml) were sequentially addeddropwise to the reaction solution, and then the reaction solution wasstirred for 30 minutes. The precipitated powder was collected byfiltration. The resulting powder was crushed with a mortar, washed withtert-butyl methyl ether and then dried under reduced pressure to obtain137.4 g of the title compound.

Then, the combined filtrate and washing solution were concentrated underreduced pressure. The residue was triturated with tert-butyl methylether and dried under reduced pressure to obtain 21.9 g of the titlecompound.

The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 4.03 (s, 3H), 7.08 (d, J=8.0 Hz, 1H), 7.61 (brs,1H), 8.47-8.51 (m, 2H).

Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide

Chloroacetone (82 ml) was added dropwise to a suspension ofN-(6-bromo-2-methoxypyridin-3-yl)formamide (159.3 g), cesium carbonate(359 g) and potassium iodide (11.4 g) in N,N-dimethylformamide (800 ml)over seven minutes. Then, the reaction solution was stirred at roomtemperature for one hour and 20 minutes.

The reaction solution was concentrated under reduced pressure. Ethylacetate and water were added to the resulting residue, and the organiclayer was separated. The resulting organic layer was washed with brine,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure to obtain 215.2 g of the title compound. The propertyvalues of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.17 (s, 3H), 4.00 (s, 3H), 4.47 (s, 2H), 7.13(d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 8.22 (s, 1H).

Synthesis of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine

A suspension of ammonium acetate (267 g) andN-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (199 g) inglacial acetic acid (400 ml) was stirred at 130° C. for one hour and 10minutes. The reaction solution was returned to room temperature. Ethylacetate and ice water were added to the reaction solution, and thereaction solution was ice-cooled. Then, concentrated aqueous ammonia(500 ml) was added dropwise and then the organic layer was separated.The resulting organic layer was sequentially washed with water and brineand dried over anhydrous magnesium sulfate. Then, the organic layer waspurified by short silica gel column chromatography (carrier: WakogelC-200; elution solvent: ethyl acetate). The eluted fraction wasconcentrated. The resulting residue was triturated with ethyl acetateand tert-butyl methyl ether and dried under reduced pressure to obtain107.7 g of the title compound.

Then, the trituration mother liquor was concentrated. The resultingresidue was purified by silica gel column chromatography (carrier:Wakogel C-200; elution solvent: toluene-ethyl acetate system). Thetarget fraction was concentrated. The resulting residue was trituratedwith tert-butyl methyl ether and dried under reduced pressure to obtain12.9 g of the title compound.

The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=0.8 Hz, 3H), 4.03 (s, 3H), 6.92 (dd,J=1.2, 0.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.73(d, J=1.2 Hz, 1H).

ESI-MS; m/z 268 [M⁺+H].

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide

Triethylamine (52 ml) was added to a suspension of6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (49.8 g),tris(dibenzylideneacetone)dipalladium (0) (5.11 g), tri-o-tolylphosphine(3.41 g) and acrylamide (14.5 g) in N,N-dimethyl formamide (260 ml). Thereaction solution was stirred at 100° C. for 50 minutes. The reactionsolution was returned to room temperature and then filtered throughcelite. The filter cake was sequentially washed withN,N-dimethylformamide, methanol, a 50% N,N-dimethylformamide solutionand N,N-dimethylformamide. The resulting filtrate was filtered throughcelite again, and the filtrate was concentrated under reduced pressure.Toluene was added to the residue, and the reaction solution wasconcentrated again. Toluene and a saturated sodium bicarbonate solutionwere added to the resulting residue, and the insoluble matter wascollected by filtration. The resulting powder was dried under reducedpressure to obtain 42.96 g of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H), 4.07 (s, 3H), 5.57 (brs,1H), 5.68 (brs, 1H), 6.98 (brs, 1H), 7.00 (d, J=15.2 Hz, 1H), 7.06 (d,J=7.6 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.56 (d, J=15.2 Hz, 1H), 7.82 (d,J=1.2 Hz, 1H).

ESI-MS; m/z 259 [M⁺+H].

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrile

Methyl dichlorophosphate (33 ml) was added dropwise to a suspension of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide(42.96 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (112 ml) in methylenechloride (400 ml) under ice-cooling over 20 minutes. The reactionsolution was stirred at the same temperature for 10 minutes and at roomtemperature for further 35 minutes. Then, a saturated sodium bicarbonatesolution (200 ml) was added to the reaction solution, and the reactionsolution was stirred at room temperature for 10 minutes. Water was addedto the reaction solution. Then, the reaction solution was filtered andthe organic layer in the filtrate was separated. The aqueous layer wasreextracted with methylene chloride (twice). The combined organic layerswere dried over anhydrous magnesium sulfate and purified by short silicagel column chromatography (carrier: Chromatorex NH; elution solvent:methylene chloride). The eluted fraction was concentrated. The resultingresidue was triturated with ethyl acetate and tert-butyl methyl etherand dried under reduced pressure overnight to obtain 34.28 g of thetitle compound.

Then, the trituration mother liquor was concentrated. The resultingresidue was triturated with acetone and dried under reduced pressure toobtain 0.56 g of the title compound.

The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 4.07 (s, 3H), 6.54 (d, J=16.0 Hz,1H), 7.00 (brs, 1H), 7.02 (d, J=7.6 Hz, 1H), 7.32 (d, J=16.0 Hz, 1H),7.57 (d, J=7.6 Hz, 1H), 7.84 (d, J=1.2 Hz, 1H).

ESI-MS; m/z 241 [M⁺+H].

Synthesis of ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride

A suspension of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrile(2.27 g) in ethanol (45 mL) was bubbled with hydrogen chloride gas underice-cooling for 20 minutes, and the reaction solution was stirred atroom temperature for 4.5 hours. The reaction solution was concentratedunder reduced pressure. Then, ethyl acetate was added to the residue,and the precipitated powder was collected by filtration. The resultingpowder was washed with ethyl acetate containing 50% of ethanol and thendried under reduced pressure to obtain 1.83 g of the title compound. Theproperty values of the compound are as follows.

ESI-MS; m/z 287 [M⁺+H-2HCl].

¹H-NMR (DMSO-D₆) δ (ppm): 1.47 (t, J=6.8 Hz, 3H), 2.35 (s, 3H), 4.06 (s,3H), 4.53 (q, J=6.8 Hz, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.64 (d, J=8.4 Hz,1H), 7.80 (brs, 1H), 7.92 (d, J=15.6 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H),9.33 (brs, 1H).

Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

A solution of 4 N hydrogen chloride in ethyl acetate (120 mL) was addedto tert-butylN′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (6.6g). The reaction solution was stirred at room temperature for one hourand then concentrated under reduced pressure to obtain4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride(6.03 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acidhydrazide hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol(10 mL) was added to a solution of ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL)at room temperature. The reaction solution was stirred at 80° C. for 25hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the resulting residue, followed by extraction withchloroform. The resulting extract was dried over magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system) to obtain 150 mg of the racemictitle compound. The racemic title compound (150 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=1:1) to obtain the title opticallyactive compound with a retention time of 13 minutes and positive opticalrotation (54 mg) and the title optically active compound with aretention time of 34 minutes and negative optical rotation (51 mg).

The property values of the title optically active compound with aretention time of 34 minutes are as follows.

ESI-MS; m/z 453 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.62-2.72 (m, 1H), 3.22-3.32 (m, 1H), 4.08 (s, 3H), 4.19-4.27 (m, 1H),4.31-4.45 (m, 2H), 6.93-7.02 (m, 4H), 7.50 (d, J=8.0 Hz, 1H), 7.53 (d,J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 13 minutes corresponded to the property values of thetitle optically active compound with a retention time of 34 minutes.

Examples 255 and 256 Synthesis of (+) and(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

Synthesis of N-(5-bromo-3-methoxypyridin-2-yl)formamide

Iron (67.3 g) and ammonium chloride (129 g) were added to a solution of5-bromo-3-methoxy-2-nitropyridine (56.0 g, CAS: 152684-26-9) in ethanol(500 mL) and water (200 mL). The reaction solution was stirred at 80 to90° C. for one hour and then left to cool to room temperature. Thereaction solution was filtered through celite and washed with ethanol.Then, the filtrate was concentrated under reduced pressure. The residuewas diluted with ethyl acetate and water, and the organic layer wasseparated. The resulting organic layer was washed with brine, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was diluted with THF (84 mL). The THF solution wasadded dropwise to a mixed solution of formic acid (78.1 mL) and aceticanhydride (78.3 mL) at room temperature. Then, the reaction solution wasstirred for one hour. Ice water (500 mL) was added to the reactionsolution, and the precipitated crystals were collected by filtration.The crystals were washed with water and then air-dried. The crystalswere recrystallized from toluene to obtain 34.1 g of the title compound.The property value of the compound is as follows.

ESI-MS; m/z 231 [M⁺+H].

Synthesis of N-(5-bromo-3-methoxypyridin-2-yl)-N-(2-oxopropyl)formamide

Cesium carbonate (96 g), potassium iodide (2.45 g) and chloroacetone(23.5 mL) were added to a solution ofN-(5-chloro-3-methoxypyridin-2-yl)formamide (34.1 g) in DMF (200 mL),and the reaction solution was stirred at 80° C. for 45 minutes. Icewater and ethyl acetate were added to the reaction solution, and theorganic layer was separated. The organic layer was washed with brine andthen dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain 52.8 g of the crude title compound. Theproperty value of the compound is as follows.

ESI-MS; m/z 287 [M⁺+H].

Synthesis of 5-bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine

A mixture of the crudeN-(5-bromo-3-methoxypyridin-2-yl)-N-(2-oxopropyl)formamide obtainedabove (26.4 g), acetic acid (52.8 mL) and ammonium acetate (35.5 g) wasstirred at 130° C. for one hour. The reaction solution was left to coolto room temperature and concentrated under reduced pressure. The residuediluted with ice water, ethyl acetate and aqueous ammonia, and theorganic layer was separated. The organic layer was washed with brine andthen dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: heptane-ethyl acetate system) to obtain5.69 g of the title compound. The property values of the compound are asfollows.

ESI-MS; m/z 268 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 3.97 (s, 3H), 7.48 (brs, 1H), 7.49(d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.30 (brs, 1H).

Synthesis of(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylonitrile

A mixture of 5-bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine(3.8 g), tris(dibenzylideneacetone)dipalladium (650 mg),tri-o-tolylphosphine (433 mg), N,N-diisopropylethylamine (4.86 mL), DMF(14.1 mL) and acrylonitrile (2.82 mL) was stirred in a nitrogenatmosphere at 110° C. for five hours. The reaction solution was left tocool to room temperature and then concentrated under reduced pressure.The residue was diluted with ethyl acetate and then filtered throughcelite, and the filtrate was washed with water. The organic layer wasconcentrated under reduced pressure, and the precipitated crystals werehot dissolved in ethyl acetate. After leaving to cool to roomtemperature, the precipitated crystals were collected by filtration andair-dried to obtain 1.79 g of the title compound. The filtrate wasconcentrated under reduced pressure. Then, the residue was purified bysilica gel column chromatography (heptane-ethyl acetate system) and thenrecrystallized from ethyl acetate to obtain 0.312 g of the titlecompound. The property value of the compound is as follows.

ESI-MS; m/z 241 [M⁺+H].

Synthesis of ethyl(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidatedihydrochloride

A suspension of(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylonitrile(2.1 g) in ethanol (40 mL) was bubbled with hydrogen chloride gas underice-cooling for one hour, and the reaction solution was stirred at roomtemperature overnight. The reaction solution was concentrated underreduced pressure. Then, ethyl acetate was added to the residue, and theprecipitated powder was collected by filtration. The resulting powderwas washed with ethyl acetate containing 50% of ethanol and then driedunder reduced pressure to obtain 1.82 g of the title compound. Theproperty values of the compound are as follows.

ESI-MS; m/z 287 [M⁺+H-2HCl].

¹H-NMR (DMSO-D₆) δ (ppm): 1.47 (t, J=6.8 Hz, 3H), 2.36 (s, 3H), 4.06 (s,3H), 4.55 (q, J=6.8 Hz, 2H), 7.26 (d, J=16.4 Hz, 1H), 8.04 (brs, 1H),8.05 (d, J=16.4 Hz, 1H), 8.21 (d, J=1.6 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H),9.61 (brs, 1H).

Synthesis of (+) and(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazidehydrochloride synthesized in Examples 253 and 254 (565 mg) andtriethylamine (1.0 mL) in ethanol (10 mL) was added to a solution ofethyl(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidatedihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL)at room temperature. The reaction solution was stirred at 80° C. for 25hours. The reaction solution was left to cool to room temperature andthen concentrated under reduced pressure. A saturated sodium bicarbonatesolution was added to the resulting residue, followed by extraction withchloroform. The resulting extract was dried over magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (carrier: Chromatorex NH; elutionsolvent: heptane-ethyl acetate system) to obtain 154 mg of the racemictitle compound. The racemic title compound (154 mg) was purified byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=1:1) and then separated by CHIRALPAK™IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=7:3) to obtain the title optically active compoundwith a retention time of 17 minutes and positive optical rotation (40mg) and the title optically active compound with a retention time of 23minutes and negative optical rotation (37 mg).

The property values of the title optically active compound with aretention time of 23 minutes are as follows.

ESI-MS; m/z 453 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.62-2.72 (m, 1H), 3.22-3.32 (m, 1H), 4.00 (s, 3H), 4.19-4.26 (m, 1H),4.31-4.45 (m, 2H), 6.93-7.02 (m, 2H), 7.11 (d, J=16.4 Hz, 1H), 7.49 (d,J=2.0 Hz, 1H), 7.53-7.55 (m, 1H), 7.58 (d, J=16.4 Hz, 1H), 8.18 (d,J=2.0 Hz, 1H), 8.36 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 17 minutes corresponded to the property values of thetitle optically active compound with a retention time of 23 minutes.

Examples 257 and 258 Synthesis of (+) and(−)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-hexahydro-[1,2,4]triazolo[5,1-c][1,4]oxazine

Synthesis of 1-[bis-(2-chloroethoxy)methyl]-4-fluorobenzene

A solution containing 4-fluorobenzaldehyde (5 g), 2-chloroethanol (13.5mL) and p-toluenesulfonic acid (767 mg) in ethanol (100 mL) was heatedunder reflux for 15 hours while dehydrating with a Dean-Stalk trap for15 hours. The reaction solution was concentrated. Ethyl acetate andsaturated sodium bicarbonate water were added to the residue, and theorganic layer was separated. The organic layer was washed with brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex NH, elution solvent: heptane/ethylacetate) to obtain the title compound (5.43 g). The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 3.67 (t, J=5.6 Hz, 4H), 3.74-3.83 (m, 4H), 7.06(dd, J=8.8, 8.8 Hz, 2H), 7.45 (dd, J=8.8, 5.6 Hz, 2H).

Synthesis of (2-chloroethoxy)-(4-fluorophenyl)acetonitrile

A solution containing 1-[bis-(2-chloroethoxy)methyl]-4-fluorobenzene(5.43 g), trimethylsilyl cyanide (4.06 mL) and tetracyanoethylene (520mg) in acetonitrile (100 mL) was heated under reflux for four hours. Thereaction solution was returned to room temperature and the solvent wasevaporated under reduced pressure. Ethyl acetate and brine were added tothe residue, and the organic layer was separated. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex, elution solvent: heptane/ethylacetate) to obtain the title compound (4.3 g). The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 3.70 (t, J=5.2 Hz, 2H), 3.82-3.87 (m, 1H),3.96-4.01 (m, 1H), 5.36 (s, 1H), 7.13 (dd, J=8.4, 8.4 Hz, 2H), 7.48-7.52(m, 2H).

Synthesis of (2-chloroethoxy)-(4-fluorophenyl)acetic acid

A mixture of (2-chloroethoxy)-(4-fluorophenyl)acetonitrile (3 g) and 5 Nhydrochloric acid was heated under reflux for 15 hours. After returningto room temperature, the reaction solution was made basic with 5 Nsodium hydroxide and washed with ether. The aqueous layer was madeacidic with 5 N hydrochloric acid. Ethyl acetate was added, and theorganic layer was separated. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto obtain the title compound (2.8 g). The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 3.68 (t, J=6.0 Hz, 2H), 3.73-3.79 (m, 1H),3.80-3.86 (m, 1H), 4.97 (s, 1H), 7.09 (dd, J=8.4, 8.4 Hz, 2H), 7.45 (dd,J=8.8, 5.2 Hz, 2H).

Synthesis of tert-butylN′-[2-(2-chloroethoxy)-2-(4-fluorophenyl)acetyl]-hydrazinecarboxylate

Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (4.38 g) was added toa solution of (2-chloroethoxy)-(4-fluorophenyl)acetic acid (2 g),tert-butyl carbazate (2.27 g) and triethylamine (3.58 mL) intetrahydrofuran (20 mL), and the reaction solution was stirred at roomtemperature for 16 hours. Saturated aqueous ammonium chloride and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(carrier: Chromatorex, elution solvent: heptane/ethyl acetate) to obtainthe title compound (2.8 g). The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.46 (s, 9H), 3.68 (t, J=6.0 Hz, 2H), 3.74-3.81(m, 2H), 4.90 (s, 1H), 7.03 (brs, 1H), 7.03-7.09 (m, 2H), 7.41-7.45 (m,2H), 8.40 (brs, 1H).

Synthesis of (+) and(−)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A solution of 4 N hydrochloric acid in ethyl acetate (5 mL) was added toa solution of tert-butylN′-[2-(2-chloroethoxy)-2-(4-fluorophenyl)acetyl]-hydrazinecarboxylate(363 mg) in ethyl acetate (5 mL). The reaction solution was stirred atroom temperature for 1.5 hours, and then the solvent was evaporatedunder reduced pressure. Ethanol (5 mL) and triethylamine (0.58 mL) wereadded to the residue. A solution of ethyl(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidatehydrochloride (300 mg) and triethylamine (0.58 mL) in ethanol (5 mL) wasadded dropwise to the mixture. The reaction solution was heated underreflux for 14 hours. The reaction solution was returned to roomtemperature and the solvent was evaporated under reduced pressure. Ethylacetate and sodium bicarbonate water were added. The organic layer wasseparated and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex NH, elution solvent: heptane/ethylacetate→ethyl acetate) to obtain a racemate of the title compound (180mg). The resulting racemate (180 mg) was optically resolved byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, elution solvent: 50% solution of hexane in ethanol) to obtain thetitle optically active compound with positive optical rotation and aretention time of 33 minutes (60 mg) and the title optically activecompound with negative optical rotation and a retention time of 42minutes (53 mg).

The property values of the title optically active compound with aretention time of 33 minutes are as follows.

ESI-MS; m/z 433 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 3.98 (s, 3H), 4.14-4.19 (m, 1H),4.31-4.42 (m, 3H), 5.92 (s, 1H), 7.08-7.13 (m, 3H), 7.43-7.48 (m, 3H),7.52-7.56 (m, 2H), 8.16 (s, 1H), 8.36 (s, 1H).

The property values of the title optically active compound with aretention time of 42 minutes are as follows.

ESI-MS; m/z 433 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 3.98 (s, 3H), 4.14-4.19 (m, 1H),4.31-4.42 (m, 3H), 5.92 (s, 1H), 7.08-7.13 (m, 3H), 7.43-7.48 (m, 3H),7.52-7.56 (m, 2H), 8.16 (s, 1H), 8.36 (s, 1H).

Examples 259 and 260 Synthesis of (+) and(−)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-1-yl]vinyl}-hexahydro-[1,2,4]triazolo[5,1-c][1,4]oxazine

Synthesis of tert-butylN′-[2-(2-chloroethoxy)-2-(4-chlorophenyl)acetyl]-hydrazinecarboxylate

The title compound (2.24 g) was obtained from 4-chlorobenzaldehyde (5 g)by the same method as in Examples 257 and 258. The property values ofthe compound are as follows.

ESI-MS; m/z 385 [M⁺+Na].

¹H-NMR (CDCl₃) δ (ppm): 1.45 (s, 9H), 3.68 (d, J=5.6 Hz, 2H), 3.75-3.82(m, 2H), 4.90 (s, 1H), 6.36 (brs, 1H), 7.33-7.41 (m, 4H), 8.39 (s, 1H).

Synthesis of 4-chlorobenzoic acid hydrazide hydrochloride

4 N hydrochloric acid-ethyl acetate (10 mL) was added to a solution oftert-butylN′-[2-(2-chloroethoxy)-2-(4-chlorophenyl)acetyl]-hydrazinecarboxylate(2.24 g) in ethyl acetate (10 mL), and the reaction solution was stirredat room temperature for six hours. The solvent was evaporated underreduced pressure to obtain the title compound (1.8 g).

¹H-NMR (CDCl₃) δ (ppm): 3.50-3.67 (m, 4H), 4.91 (s, 1H), 7.25-7.32 (m,4H).

Synthesis of (+) and(−)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-1-yl]vinyl}-hexahydro-[1,2,4]triazolo[5,1-c][1,4]oxazine

A solution of 4-chlorobenzoic acid hydrazide hydrochloride (250 mg) andtriethylamine (0.58 mL) in ethanol (5 mL) was added dropwise to asolution of ethyl(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidatehydrochloride (250 mg) and triethylamine (0.58 mL) in ethanol (5 mL).The reaction solution was heated under reflux for 14 hours. The reactionsolution was returned to room temperature and the solvent was evaporatedunder reduced pressure. Ethyl acetate and sodium bicarbonate water wereadded. The organic layer was separated and washed with brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (carrier: Chromatorex NH, elutionsolvent: heptane/ethyl acetate→ethyl acetate) to obtain a racemate ofthe title compound (145 mg). The resulting racemate (145 mg) wasoptically resolved by CHIRALPAK™ IA manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, elution solvent: 50% solution of hexane inethanol, flow rate: 10 mL/min) to obtain the title optically activecompound with positive optical rotation and a retention time of 14.7minutes (analysis conditions: CHIRALPAK™ IA manufactured by DaicelChemical Industries, Ltd. (0.46 cm×25 cm, elution solvent: 50% solutionof hexane in ethanol, flow rate: 1 mL/min) (40 mg) and the titleoptically active compound with negative optical rotation and a retentiontime of 16.4 minutes (analysis conditions: CHIRALPAK™ IA manufactured byDaicel Chemical Industries, Ltd. (0.46 cm×25 cm, elution solvent: 50%solution of hexane in ethanol, flow rate: 1 mL/min) (54 mg).

The property values of the title optically active compound with aretention time of 14.7 minutes are as follows.

ESI-MS; m/z 449 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=1.2 Hz, 3H), 3.98 (s, 3H), 4.14-4.31(m, 1H), 4.29-4.40 (m, 3H), 5.90 (s, 1H), 7.08 (d, J=16.0 Hz, 1H),7.37-7.43 (m, 4H), 7.46 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.52 (d, J=16.0Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 16.4 minutes are as follows.

ESI-MS; m/z 449 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=1.2 Hz, 3H), 3.98 (s, 3H), 4.14-4.31(m, 1H), 4.29-4.40 (m, 3H), 5.90 (s, 1H), 7.08 (d, J=16.0 Hz, 1H),7.37-7.43 (m, 4H), 7.46 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.52 (d, J=16.0Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).

Examples 261 and 262 Synthesis of (+) and(−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine

Synthesis of (+) and(−)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A solution of 4-chlorobenzoic acid hydrazide hydrochloride (250 mg) andtriethylamine (0.58 mL) in ethanol (5 mL) was added dropwise to asolution of ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatehydrochloride (300 mg) and triethylamine (0.58 mL) in ethanol (5 mL).The reaction solution was heated under reflux for 14 hours. The reactionsolution was returned to room temperature and the solvent was evaporatedunder reduced pressure. Ethyl acetate and sodium bicarbonate water wereadded. The organic layer was separated and washed with brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (carrier: Chromatorex NH, elutionsolvent: heptane/ethyl acetate→ethyl acetate) to obtain a racemate ofthe title compound (170 mg). The resulting racemate (170 mg) wasoptically resolved by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, elution solvent: ethanol, flow rate: 10mL/min) to obtain the title optically active compound with positiveoptical rotation and a retention time of 16 minutes (68 mg) and thetitle optically active compound with negative optical rotation and aretention time of 25 minutes (63 mg).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 449 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=1.2 Hz, 3H), 4.06 (s, 3H), 4.11-4.20(m, 1H), 4.28-4.42 (m, 3H), 5.92 (s, 1H), 6.96 (s, 1H), 6.96 (d, J=7.6Hz, 1H), 7.38-7.44 (m, 4H), 7.47 (d, J=7.6 Hz, 1H), 7.50 (d, J=16.0 Hz,1H), 7.65 (d, J=16.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 25 minutes are as follows.

ESI-MS; m/z 449 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.29 (d, J=1.2 Hz, 3H), 4.06 (s, 3H), 4.11-4.20(m, 1H), 4.28-4.42 (m, 3H), 5.92 (s, 1H), 6.96 (s, 1H), 6.96 (d, J=7.6Hz, 1H), 7.38-7.44 (m, 4H), 7.47 (d, J=7.6 Hz, 1H), 7.50 (d, J=16.0 Hz,1H), 7.65 (d, J=16.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The following compounds were obtained using ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride by the same method as in Examples 257 and 258 (Table 8).

TABLE 8

Example E₃ DATA: MS m/z Note 263

M⁺ + H: 432 (ESI) Optically active compound (separation conditions IB:retention time 22 min, optical rotation (+)) 264

M⁺ + H: 432 (ESI) Optically active compound (separation conditions IB:retention time 27 min, optical rotation (−)) 265

M⁺ + H: 448 (ESI) Optically active compound (separation conditions IA:retention time 31 min, optical rotation (+)) 266

M⁺ + H: 448 (ESI) Optically active compound (separation conditions IA:retention time 35 min, optical rotation (−)) 267

M⁺ + H: 482 (ESI) Optically active compound (separation conditions IA:retention time 19 min, optical rotation (+)) 268

M⁺ + H: 482 (ESI) Optically active compound (separation conditions IA:retention time 25 min, optical rotation (−)) 269

M⁺ + H: 457 (ESI) Optically active compound (separation conditions OJ-H:retention time 11 min, optical rotation (−)) 270

M⁺ + H: 457 (ESI) Optically active compound (separation conditions OJ-H:retention time 27 min, optical rotation (+)) 271

M⁺ + H: 414 (ESI) Optically active compound (separation conditions AD-H:retention time 10 min, optical rotation (−)) 272

M⁺ + H: 414 (ESI) Optically active compound (separation conditions AD-H:retention time 12 min, optical rotation (+)) 273

M⁺ + H: 446 (ESI) Optically active compound (separation conditionsAD-H:ethanol: retention time 30 min, optical rotation (−)) 274

M⁺ + H: 446 (ESI) Optically active compound (separation conditionsAD-H:ethanol: retention time 36 min, optical rotation (+))

Examples 275 and 276 Synthesis of (+) and(−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine

Synthesis of (+) and(−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A solution of 4 N hydrochloric acid in ethyl acetate (5 mL) was added toa solution of tert-butylN′-[2-(2-chloroethoxy)-2-(4-fluorophenyl)acetyl]-hydrazinecarboxylate(363 mg) in ethyl acetate (5 mL). The reaction solution was stirred atroom temperature for 1.5 hours, and then the solvent was evaporatedunder reduced pressure. Ethanol (5 mL) and triethylamine (0.58 mL) wereadded to the residue. A solution of ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatehydrochloride (300 mg) and triethylamine (0.58 mL) in ethanol (5 mL) wasadded dropwise to the mixture. Then, the reaction solution was heatedunder reflux for 14 hours. The reaction solution was returned to roomtemperature and the solvent was evaporated under reduced pressure. Ethylacetate and sodium bicarbonate water were added. The organic layer wasseparated and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (carrier: Chromatorex NH, elution solvent: heptane/ethylacetate→ethyl acetate) to obtain a racemate of the title compound (130mg). The resulting racemate (130 mg) was optically resolved byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, elution solvent: ethanol) to obtain the title optically activecompound with positive optical rotation and a retention time of 17minutes (28 mg) and the title optically active compound with negativeoptical rotation and a retention time of 26 minutes (35 mg).

The property values of the title optically active compound with aretention time of 17 minutes are as follows.

ESI-MS; m/z 433 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 4.06 (s, 3H), 4.13-4.20 (m, 1H),4.29-4.41 (m, 3H), 5.93 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.97 (s, 1H),7.11 (dd, J=8.8, 8.4 Hz, 2H), 7.45 (dd, J=8.8, 5.2 Hz, 2H), 7.48 (d,J=15.6 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78(s, 1H).

The property values of the title optically active compound with aretention time of 26 minutes are as follows.

ESI-MS; m/z 433 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 4.06 (s, 3H), 4.13-4.20 (m, 1H),4.29-4.41 (m, 3H), 5.93 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.97 (s, 1H),7.11 (dd, J=8.8, 8.4 Hz, 2H), 7.45 (dd, J=8.8, 5.2 Hz, 2H), 7.48 (d,J=15.6 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78(s, 1H).

Examples 277 and 278 Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(300 mg) and 1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one (180 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=80:20) toobtain the title optically active compound with a retention time of 8.9minutes and positive optical rotation (79.9 mg, >99% ee) and the titleoptically active compound with a retention time of 19.8 minutes andnegative optical rotation (73.0 mg, >99% ee).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.07-2.19 (m, 2H), 2.29(s, 3H), 2.29-2.36 (m, 2H), 4.03 (s, 3H), 4.23-4.28 (m, 1H), 4.35-4.39(m, 1H), 4.54-4.59 (m, 1H), 6.66-6.72 (m, 2H), 6.93 (d, J=8.0 Hz, 1H),6.95 (s, 1H), 7.40 (d, J=16.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.62 (d,J=16.0 Hz, 1H), 7.76 (s, 1H).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.07-2.19 (m, 2H), 2.29(s, 3H), 2.29-2.36 (m, 2H), 4.03 (s, 3H), 4.23-4.28 (m, 1H), 4.35-4.39(m, 1H), 4.54-4.59 (m, 1H), 6.66-6.72 (m, 2H), 6.93 (d, J=8.0 Hz, 1H),6.95 (s, 1H), 7.40 (d, J=16.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.62 (d,J=16.0 Hz, 1H), 7.76 (s, 1H).

Examples 279 and 280 Synthesis of(+)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(300 mg) and 1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one (160 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 3.5 minutes andpositive optical rotation (53.8 mg, >99% ee) and the title opticallyactive compound with a retention time of 4.3 minutes and negativeoptical rotation (54.2 mg, >99% ee).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 449 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.24 (m, 3H), 2.29(s, 3H), 2.37-2.43 (m, 1H), 4.05 (s, 3H), 4.31 (t, J=6.0 Hz, 2H), 4.62(t, J=6.4 Hz, 1H), 6.73 (t, J=6.8 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.96(s, 1H), 7.01-7.14 (m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.47 (d, J=8.0 Hz,1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 449 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.24 (m, 3H), 2.29(s, 3H), 2.37-2.43 (m, 1H), 4.05 (s, 3H), 4.31 (t, J=6.0 Hz, 2H), 4.62(t, J=6.4 Hz, 1H), 6.73 (t, J=6.8 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.96(s, 1H), 7.01-7.14 (m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.47 (d, J=8.0 Hz,1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).

Examples 281 and 282 Synthesis of(+)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (44.5 mg) was obtained using1-amino-3-(2-fluoro-3-methylphenyl)piperidin-2-one (150 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (44.5 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol,flow rate: 12 mL/min) to obtain the title optically active compound witha retention time of 13 minutes and positive optical rotation (17 mg) andthe title optically active compound with a retention time of 19 minutesand negative optical rotation (15 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.12-2.24 (m, 3H), 2.28 (s, 3H), 2.29 (s, 3H),2.32-2.40 (m, 1H), 4.04 (s, 3H), 4.23-4.36 (m, 2H), 4.59 (dd, J=6.6, 6.6Hz, 1H), 6.72-6.78 (m, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.94-6.96 (m, 1H),6.99 (d, J=7.7 Hz, 1H), 7.09-7.14 (m, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.47(d, J=7.7 Hz, 1H), 7.65 (d, J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H).

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.12-2.24 (m, 3H), 2.28 (s, 3H), 2.29 (s, 3H),2.32-2.40 (m, 1H), 4.04 (s, 3H), 4.23-4.36 (m, 2H), 4.59 (dd, J=6.6, 6.6Hz, 1H), 6.72-6.78 (m, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.94-6.96 (m, 1H),6.99 (d, J=7.7 Hz, 1H), 7.09-7.14 (m, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.47(d, J=7.7 Hz, 1H), 7.65 (d, J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H).

Examples 283 and 284 Synthesis of(−)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-trifluoromethoxyphenyl)piperidin-2-one

520 mg of the title compound was obtained using2-trifluoromethoxyphenylacetic acid (1 g) as a starting materialaccording to the method in Examples 20 and 21. The property value of thecompound is as follows.

ESI-MS; m/z 275 [M⁺+H].

Synthesis of(−)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (146 mg) was obtained from1-amino-3-(2-trifluoromethoxyphenyl)piperidin-2-one (300 mg) accordingto the method in Examples 168 and 169. The resulting racemate (146 mg)was separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=8:2, flowrate: 11 mL/min) to obtain the title optically active compound with aretention time of 32 minutes and negative optical rotation (49.9 mg) andthe title optically active compound with a retention time of 46 minutesand positive optical rotation (47.2 mg).

The property values of the title optically active compound with aretention time of 32 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.41 (m, 7H), 4.04 (s, 3H), 4.28-4.32 (m,2H), 4.64 (m, 1H), 6.92-6.99 (m, 3H), 7.19-7.35 (m, 3H), 7.44 (d, J=15.2Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 46 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.41 (m, 7H), 4.04 (s, 3H), 4.28-4.32 (m,2H), 4.64 (m, 1H), 6.92-6.99 (m, 3H), 7.19-7.35 (m, 3H), 7.44 (d, J=15.2Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.76 (s, 1H).

Examples 285 and 286 Synthesis of(+)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-trifluoromethyl-4-fluorophenyl)piperidin-2-one

364 mg of the title compound was obtained using2-trifluoromethyl-4-fluorophenylacetic acid (1 g) as a starting materialaccording to the method in Examples 194 and 195. The property value ofthe compound is as follows.

ESI-MS; m/z 277 [M⁺+H].

Synthesis of(+)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (190 mg) was obtained using1-amino-3-(2-trifluoromethyl-4-fluorophenyl)piperidin-2-one (360 mg) asa starting material according to the method in Examples 168 and 169. Theresulting racemate (149 mg) was separated by CHIRALPAK™ IA manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase:hexane:ethanol=8:2, flow rate: 11 mL/min) to obtain the title opticallyactive compound with a retention time of 25 minutes and positive opticalrotation (83.6 mg) and the title optically active compound with aretention time of 30 minutes and negative optical rotation (82.8 mg).

The property values of the title optically active compound with aretention time of 25 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.86-2.48 (m, 7H), 4.03 (s, 3H), 4.27-4.40 (m,2H), 4.64 (dd, J=8.8, 6.0 Hz, 1H), 6.92-7.04 (m, 3H), 7.19 (t, J=8.0 Hz,1H), 7.40-7.47 (m, 3H), 7.62 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 30 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.86-2.48 (m, 7H), 4.03 (s, 3H), 4.27-4.40 (m,2H), 4.64 (dd, J=8.8, 6.0 Hz, 1H), 6.92-7.04 (m, 3H), 7.19 (t, J=8.0 Hz,1H), 7.40-7.47 (m, 3H), 7.62 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).

Examples 287 and 288 Synthesis of(−)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-octahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-octahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of (2-difluoromethoxyphenyl)acetonitrile

A solution of p-toluenesulfonylmethyl isocyanide (2.4 g) indimethoxyethane (10 mL) was added to a solution of potassiumtert-butoxide (2.68 g) in dimethoxyethane (30 mL) at −35° C., and thereaction solution was stirred at the same temperature for 10 minutes.The reaction solution was cooled to −55° C. A solution ofdifluoromethoxybenzaldehyde (2 g) in dimethoxyethane (5 mL) was addeddropwise, and the reaction solution was stirred at the same temperaturefor two hours. 10 mL of methanol was added to the reaction solution, andthe reaction solution was heated under reflux for 15 minutes. Thereaction solution was left to cool to room temperature. Then, water anddichloromethane were added and the organic layer was separated. Theresulting organic layer was dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: heptane-ethyl acetatesystem) to obtain 1.45 g of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 3.78 (s, 2H), 6.58 (t, J=73.2 Hz, 1H), 7.17 (d,J=8.4 Hz, 1H), 7.26 (t, J=7.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.51 (d,J=7.6 Hz, 1H).

Synthesis of ethyl (2-difluoromethoxyphenyl)acetate

(2-Difluoromethoxyphenyl)acetonitrile (1.45 g) was added dropwise to asolution of chlorotrimethylsilane (2.23 mL) in ethanol (2.0 mL), and thereaction solution was stirred at 50° C. for five hours. The reactionsolution was left to cool to room temperature. Then, potassiumcarbonate, water and ethyl acetate were added and the organic layer wasseparated. The resulting organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elutionsolvent: heptane-ethyl acetate system) to obtain 620 mg of the titlecompound. The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.26 (t, J=7.2 Hz, 3H), 3.68 (s, 2H), 4.16 (q,7.2 Hz, 2H), 6.48 (t, J=74.4 Hz, 1H), 7.13-7.32 (m, 4H).

Synthesis of 1-amino-3-(2-difluoromethoxyphenyl)piperidin-2-one

395 mg of the title compound was obtained using ethyl2-difluoromethoxyphenylacetate (630 mg) as a starting material accordingto the method in Examples 20 and 21. The property value of the compoundis as follows.

ESI-MS; m/z 257 [M⁺+H].

Synthesis of(−)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (105 mg) was obtained from1-amino-3-(2-difluoromethoxyphenyl)piperidin-2-one (395 mg) according tothe method in Examples 168 and 169. The resulting racemate (105 mg) wasseparated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=8:2, flow rate: 13mL/min) to obtain the title optically active compound with a retentiontime of 45 minutes and negative optical rotation (48.1 mg) and the titleoptically active compound with a retention time of 69 minutes andpositive optical rotation (41 mg).

The property values of the title optically active compound with aretention time of 45 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.37 (m, 7H), 4.04 (s, 3H), 4.24-4.35 (m,2H), 4.55 (m, 1H), 6.43 (t, J=74.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.95(s, 1H), 7.04-7.20 (m, 3H), 7.31 (t, J=7.8 Hz, 1H), 7.41 (d, J=16.0 Hz,1H), 7.45 (d, J=8.0 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.60 (s, 1H).

The property values of the title optically active compound with aretention time of 69 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.37 (m, 7H), 4.04 (s, 3H), 4.24-4.35 (m,2H), 4.55 (m, 1H), 6.43 (t, J=74.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.95(s, 1H), 7.04-7.20 (m, 3H), 7.31 (t, J=7.8 Hz, 1H), 7.41 (d, J=16.0 Hz,1H), 7.45 (d, J=8.0 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.60 (s, 1H).

Examples 289 and 290 Synthesis of(+)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-bromophenyl)piperidin-2-one

820 mg of the title compound was obtained using 2-bromophenylacetic acid(1 g) as a starting material according to the method in Examples 20 and21. The property value of the compound is as follows.

ESI-MS; m/z 269 [M⁺+H].

Synthesis of(+)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (210 mg) was obtained from1-amino-3-(2-bromophenyl)piperidin-2-one (300 mg) according to themethod in Examples 168 and 169. The resulting racemate (210 mg) wasseparated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 13 mL/min) to obtainthe title optically active compound with a retention time of 14.5minutes and positive optical rotation (78.6 mg) and the title opticallyactive compound with a retention time of 19.2 minutes and negativeoptical rotation (68 mg).

The property values of the title optically active compound with aretention time of 14.5 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.42 (m, 7H), 4.04 (s, 3H), 4.24-4.36 (m,2H), 4.76 (m, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.95(s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.45 (d, J=16.0Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.65 (d, J=16.0Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 19.2 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.42 (m, 7H), 4.04 (s, 3H), 4.24-4.36 (m,2H), 4.76 (m, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.95(s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.45 (d, J=16.0Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.65 (d, J=16.0Hz, 1H), 7.76 (s, 1H).

Examples 291 and 292 Synthesis of(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(300 mg) and 1-amino-3-(4-methoxyphenyl)piperidin-2-one (163 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 4.1 minutes andpositive optical rotation (76.4 mg, >99% ee) and the title opticallyactive compound with a retention time of 4.7 minutes and negativeoptical rotation (78.2 mg, >99% ee).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 443 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.09 (m, 2H),2.16-2.22 (m, 1H), 2.29 (s, 3H), 2.29-2.37 (m, 1H), 3.80 (s, 3H), 4.05(s, 3H), 4.24-4.33 (m, 3H), 6.87 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.0 Hz,1H), 6.96 (s, 1H), 7.06 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.47(d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 443 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.09 (m, 2H),2.16-2.22 (m, 1H), 2.29 (s, 3H), 2.29-2.37 (m, 1H), 3.80 (s, 3H), 4.05(s, 3H), 4.24-4.33 (m, 3H), 6.87 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.0 Hz,1H), 6.96 (s, 1H), 7.06 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.47(d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).

Examples 293 and 294 Synthesis of(+)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(3-fluoro-2-methylphenyl)piperidin-2-one

521 mg of the title compound was obtained according to the method inExamples 20 and 21 through ethyl 3-fluoro-2-methylphenylacetate as anintermediate from 3-fluoro-2-methylbenzaldehyde (1.5 g) as a startingmaterial according to the method in Examples 40 and 41. The propertyvalue of the compound is as follows.

ESI-MS; m/z 223 [M⁺+H].

Synthesis of(+)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (34.8 mg) was obtained using1-amino-3-(3-fluoro-2-methylphenyl)piperidin-2-one (171 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (34.8 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase:ethanol:hexane=3:7, flow rate: 20 mL/min) to obtain the title opticallyactive compound with a retention time of 9 minutes and positive opticalrotation (12 mg) and the title optically active compound with aretention time of 15 minutes and negative optical rotation (15 mg).

The property values of the title optically active compound with aretention time of 9 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.94-2.03 (m, 1H), 2.04-2.15 (m, 1H), 2.16-2.38(m, 2H), 2.29 (s, 3H), 2.30 (s, 3H), 3.97 (s, 3H), 4.29 (ddd, J=12.5,12.5, 5.8 Hz, 1H), 4.33 (ddd, J=12.5, 12.5, 5.5 Hz, 1H), 4.54 (t, J=6.2Hz, 1H), 6.54 (d, J=7.7 Hz, 1H), 6.93-7.00 (m, 1H), 7.06-7.13 (m, 1H),7.09 (d, J=16.1 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.51 (d, J=16.1 Hz,1H), 7.52 (d, J=1.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz,1H).

The property values of the title optically active compound with aretention time of 15 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.94-2.03 (m, 1H), 2.04-2.15 (m, 1H), 2.16-2.38(m, 2H), 2.29 (s, 3H), 2.30 (s, 3H), 3.97 (s, 3H), 4.29 (ddd, J=12.5,12.5, 5.8 Hz, 1H), 4.33 (ddd, J=12.5, 12.5, 5.5 Hz, 1H), 4.54 (t, J=6.2Hz, 1H), 6.54 (d, J=7.7 Hz, 1H), 6.93-7.00 (m, 1H), 7.06-7.13 (m, 1H),7.09 (d, J=16.1 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.51 (d, J=16.1 Hz,1H), 7.52 (d, J=1.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz,1H).

Examples 295 and 296 Synthesis of(+)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of ethyl (2-fluoro-3-methylphenyl)acetate

A mixture of 2-fluoro-3-methylbenzyl bromide (2.0 g), sodium cyanide(2.41 g), sodium iodide (148 mg) and DMSO (10 ml) was stirred at 60° C.for two hours. Water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The organic layer waswashed with brine. The resulting organic layer was dried over anhydrousmagnesium sulfate. The organic layer was concentrated under reducedpressure. 5 N hydrochloric acid (15 ml) was added to the residue, andthe reaction solution was heated at 110° C. for 22 hours. The reactionsolution was brought to room temperature. Chloroform was added and theorganic layer was separated. The organic layer was concentrated underreduced pressure. Saturated hydrogen chloride-ethanol (15 ml) was addedto the residue, and the reaction solution was stirred at 85° C. for fourhours. The reaction solution was concentrated under reduced pressure,and then diluted with ethyl acetate and washed with saturated sodiumbicarbonate water and then with brine. The resulting organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to obtain the title compound (1.1 g). The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.24 (t, J=6.9 Hz, 3H), 2.27 (s, 3H), 3.65 (s,2H), 4.15 (q, J=6.9 Hz, 2H), 6.96-7.01 (m, 1H), 7.05-7.13 (m, 2H).

Synthesis of 1-amino-3-(2-fluoro-3-methylphenyl)piperidin-2-one

766 mg of the title compound was obtained using ethyl(2-fluoro-3-methylphenyl)acetate (1.1 g) as a starting materialaccording to the method in Examples 20 and 21. The property value of thecompound is as follows.

ESI-MS; m/z 223 [M⁺+H].

Synthesis of(+)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (161.8 mg) was obtained using1-amino-3-(2-fluoro-3-methylphenyl)piperidin-2-one (250 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (34.8 mg) was separated by CHIRALPAK™ AD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: ethanol, flow rate: 12 mL/min) to obtain the title opticallyactive compound with a retention time of 18 minutes and negative opticalrotation (75 mg) and the title optically active compound with aretention time of 28 minutes and positive optical rotation (70 mg).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.10-2.40 (m, 4H), 2.28 (s, 3H), 2.29 (s, 3H),3.96 (s, 3H), 4.23-4.26 (m, 2H), 4.57 (dd, J=7.0, 5.7 Hz, 1H), 6.73-6.77(m, 1H), 6.98 (dd, J=7.3, 7.3 Hz, 1H), 7.10 (d, J=16.1 Hz, 1H),7.09-7.14 (m, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.51 (d, J=16.1 Hz, 1H), 7.52(d, J=1.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H).

The property values of the title optically active compound with aretention time of 15 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.10-2.40 (m, 4H), 2.28 (s, 3H), 2.29 (s, 3H),3.96 (s, 3H), 4.23-4.26 (m, 2H), 4.57 (dd, J=7.0, 5.7 Hz, 1H), 6.73-6.77(m, 1H), 6.98 (dd, J=7.3, 7.3 Hz, 1H), 7.10 (d, J=16.1 Hz, 1H),7.09-7.14 (m, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.51 (d, J=16.1 Hz, 1H), 7.52(d, J=1.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H).

Examples 297 and 298 Synthesis of(−)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2,3-difluorophenyl)piperidin-2-one

2.06 g of the title compound was obtained from methyl2,3-difluorophenylacetate (5.63 g) according to the method in Examples20 and 21. The property value of the compound is as follows.

ESI-MS; m/z 227 [M⁺+H].

Synthesis of(−)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(250 mg) and 1-amino-3-(2,3-difluorophenyl)piperidin-2-one (167 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 7.9 minutes andnegative optical rotation (27.3 mg, >99% ee) and the title opticallyactive compound with a retention time of 12 minutes and positive opticalrotation (27.1 mg, >99% ee).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 449 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.28 (m, 3H), 2.29(s, 3H), 2.36-2.43 (m, 1H), 3.97 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.60(t, J=6.0 Hz, 1H), 6.75 (dd, J=8.0, 6.0 Hz, 1H), 7.00-7.15 (m, 3H), 7.45(s, 1H), 7.49 (d, J=15.6 Hz, 1H), 7.52 (s, 1H), 8.15 (s, 1H), 8.34 (s,1H).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 449 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.28 (m, 3H), 2.29(s, 3H), 2.36-2.43 (m, 1H), 3.97 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.60(t, J=6.0 Hz, 1H), 6.75 (dd, J=8.0, 6.0 Hz, 1H), 7.00-7.15 (m, 3H), 7.45(s, 1H), 7.49 (d, J=15.6 Hz, 1H), 7.52 (s, 1H), 8.15 (s, 1H), 8.34 (s,1H).

Examples 299 and 300 Synthesis of(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(4-methoxyphenyl)piperidin-2-one

0.910 g of the title compound was obtained from methyl4-methoxyphenylacetate (5 g) according to the method in Examples 20 and21. The property value of the compound is as follows.

ESI-MS; m/z 221 [M⁺+H].

Synthesis of(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(250 mg) and 1-amino-3-(4-methoxyphenyl)piperidin-2-one (162 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 14 minutes andnegative optical rotation (9.6 mg, >99% ee) and the title opticallyactive compound with a retention time of 20 minutes and positive opticalrotation (10.4 mg, >99% ee).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 443 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.17 (m, 2H),2.18-2.28 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.30-2.39 (m, 1H), 3.80 (s,3H), 3.97 (s, 3H), 4.25-4.32 (m, 3H), 6.85-6.90 (m, 2H), 7.04-7.07 (m,2H), 7.10 (d, J=16.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.51 (d, J=16.0Hz, 1H), 7.52 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 443 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.17 (m, 2H),2.18-2.28 (m, 1H), 2.29 (d, J=1.2 Hz, 3H), 2.30-2.39 (m, 1H), 3.80 (s,3H), 3.97 (s, 3H), 4.25-4.32 (m, 3H), 6.85-6.90 (m, 2H), 7.04-7.07 (m,2H), 7.10 (d, J=16.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.51 (d, J=16.0Hz, 1H), 7.52 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).

Examples 301 and 302 Synthesis of(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(250 mg) and 1-amino-3-(4-methoxyphenyl)piperidin-2-one (180 mg)according to the method in Examples 168 and 169. The resulting racematewas separated by CHIRALPAK™ AD-H manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 6.4 minutes andnegative optical rotation (48.6 mg, >99% ee) and the title opticallyactive compound with a retention time of 8.1 minutes and positiveoptical rotation (47.7 mg, >99% ee).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.20 (m, 3H), 2.29(s, 3H), 2.29-2.37 (m, 1H), 3.96 (s, 3H), 4.19-4.27 (m, 1H), 4.34-4.40(m, 1H), 4.54-4.58 (m, 1H), 6.70 (t, J=8.4 Hz, 2H), 7.06 (d, J=16.0 Hz,1H), 7.45 (d, J=16.0 Hz, 1H), 7.46 (s, 1H), 7.52 (s, 1H), 8.13 (s, 1H),8.34 (s, 1H).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.04-2.20 (m, 3H), 2.29(s, 3H), 2.29-2.37 (m, 1H), 3.96 (s, 3H), 4.19-4.27 (m, 1H), 4.34-4.40(m, 1H), 4.54-4.58 (m, 1H), 6.70 (t, J=8.4 Hz, 2H), 7.06 (d, J=16.0 Hz,1H), 7.45 (d, J=16.0 Hz, 1H), 7.46 (s, 1H), 7.52 (s, 1H), 8.13 (s, 1H),8.34 (s, 1H).

Examples 303 and 304 Synthesis of(+)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(63.2 mg) and 1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one (91.1mg) according to the method in Examples 220 and 221. The resultingracemate was separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 6.4 minutes andnegative optical rotation (6.2 mg, >99% ee) and the title opticallyactive compound with a retention time of 7.6 minutes and positiveoptical rotation (5.5 mg, >99% ee).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 509 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.95-2.05 (m, 1H),2.06-2.12 (m, 2H), 2.30 (d, J=0.8 Hz, 3H), 2.35-2.42 (m, 1H), 3.90 (s,3H), 4.31 (t, J=6.0 Hz, 2H), 4.71 (t, J=6.8 Hz, 1H), 6.85-6.91 (m, 1H),6.91 (d, J=0.8 Hz, 1H), 6.98 (dd, J=8.0, 2.4 Hz, 1H), 7.00 (d, J=1.2 Hz,1H), 7.36 (dd, J=8.0, 2.8 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.60 (d,J=16.0 Hz, 1H), 7.68 (d, J=1.2 Hz, 1H), 8.42 (s, 1H).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 509 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.95-2.05 (m, 1H),2.06-2.12 (m, 2H), 2.30 (d, J=0.8 Hz, 3H), 2.35-2.42 (m, 1H), 3.90 (s,3H), 4.31 (t, J=6.0 Hz, 2H), 4.71 (t, J=6.8 Hz, 1H), 6.85-6.91 (m, 1H),6.91 (d, J=0.8 Hz, 1H), 6.98 (dd, J=8.0, 2.4 Hz, 1H), 7.00 (d, J=1.2 Hz,1H), 7.36 (dd, J=8.0, 2.8 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.60 (d,J=16.0 Hz, 1H), 7.68 (d, J=1.2 Hz, 1H), 8.42 (s, 1H).

Example 305 Synthesis of2-(4-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

(1) Synthesis of5-chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-pentanoicacid hydrazide

5-Chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]pentanoicacid (CAS No. 870843-27-9, 10 g) was dissolved in dichloromethane (130mL). BOPCl (4.53 g), IPEA (12.3 g) and tert-butyl carbazate (2.82 g)were added and the reaction solution was stirred at room temperature forthree hours. Water and ethyl acetate were added to the reactionsolution, and the organic layer was separated. The organic layer waswashed with a 1 N sodium hydroxide solution and 1 N hydrochloric acid inthis order. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. A solution of 4 N hydrochloric acidin ethyl acetate (100 mL) was added to the residue, and the reactionsolution was stirred at room temperature for two hours. The reactionsolution was concentrated under reduced pressure to obtain 3.87 g of acrude product of the title compound. The property value of the compoundis as follows.

ESI-MS; m/z 349 [M⁺+H].

(2) Synthesis of2-(4-bromophenyl)-N-{3-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-2-oxopiperidin-1-yl}acetamide

EDC (109 mg), HOBT (76.9 mg) and IPEA (408 μL) were added to a mixtureof 4-bromophenylacetic acid (102 mg),5-chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-pentanoicacid hydrazide (200 mg) and DMF (4 mL), and the reaction solution wasstirred at room temperature for 14 hours. The reaction solution washeated to 80° C. and stirred for two hours. The reaction solution wasbrought to room temperature. A saturated sodium bicarbonate solution wasadded, followed by separatory extraction with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography(carrier: Chromatorex NH; elution solvent: heptane:ethylacetate=1:1→ethyl acetate→ethyl acetate:methanol=8:1) to obtain thetitle compound (111 mg). The property value of the compound is asfollows.

ESI-MS; m/z 508 [M⁺+H].

(3) Synthesis of2-(4-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Phosphorus oxychloride (2.4 mL) was added to2-(4-bromophenyl)-N-{3-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-2-oxopiperidin-1-yl}acetamide(111 mg), and the reaction solution was stirred at 100° C. for one hour.The reaction solution was concentrated under reduced pressure. Theresidue was diluted with acetic acid (1 mL) and then ammonium acetate(336 mg) was added. The reaction solution was stirred at 140° C. for onehour and 30 minutes. Ethyl acetate and a sodium bicarbonate solutionwere added to the reaction solution, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography (carrier: Chromatorex NH; elution solvent:heptane:ethyl acetate=2:1→ethyl acetate) to obtain the title compound(50 mg). The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.11-2.16 (m, 2H), 2.30 (s, 3H), 2.92-2.95 (m,2H), 3.85 (s, 3H), 4.04 (s, 2H), 4.22 (t, J=4 Hz, 2H), 6.93 (s, 1H),7.03-7.06 (m, 2H), 7.24-7.26 (m, 3H), 7.41-7.44 (m, 2H), 7.66 (s, 1H),7.72 (s, 1H).

Example 306 Synthesis of2-(3-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

The title compound (38 mg) was obtained using 3-bromophenylacetic acid(102 mg) as a starting material according to the method in Example 305.

The property values of the title compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.11-2.17 (m, 2H), 2.30 (s, 3H), 2.92-2.96 (m,2H), 3.85 (s, 3H), 4.06 (s, 2H), 4.24 (t, J=5.6 Hz, 2H), 6.93 (s, 1H),7.03-7.07 (m, 2H), 7.16-7.36 (m, 4H), 7.51 (s, 2H), 7.67 (s, 1H), 7.72(s, 1H).

Example 307 Synthesis of2-(2-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

The title compound (43 mg) was obtained using 2-bromophenylacetic acid(102 mg) as a starting material according to the method in Example 305.

The property values of the title compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.11-2.17 (m, 2H), 2.30 (s, 3H), 2.93-2.96 (m,2H), 3.85 (s, 3H), 4.22-4.25 (m, 4H), 6.93 (s, 1H), 7.04-7.13 (m, 3H),7.25-7.34 (m, 3H), 7.56-7.59 (m, 1H), 7.68 (s, 1H), 7.70 (s, 1H).

Examples 308 and 309 Synthesis of2-[(S)-1-(4-fluorophenyl)ethyl]-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand2-[(R)-1-(4-fluorophenyl)ethyl]-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (64 mg) was obtained using4-fluoro-α-methyl-phenylacetic acid (109 mg) as a starting materialaccording to the method in Example 305. The resulting racemate (64 mg)was separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=8:2, flowrate: 10 mL/min) to obtain the title optically active compound with aretention time of 26 minutes and positive optical rotation (15 mg) andthe title optically active compound with a retention time of 31 minutesand negative optical rotation (16 mg).

The property values of the title optically active compound with aretention time of 26 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.70 (d, J=7.2 Hz, 3H), 2.10-2.16 (m, 2H), 2.23(m, 3H), 2.90-2.94 (m, 2H), 3.85 (s, 3H), 4.22-4.30 (m, 3H), 6.93-7.06(m, 5H), 7.24 (s, 1H), 7.35-7.38 (m, 2H), 7.66 (s, 1H), 7.71 (s, 1H).

The property values of the title optically active compound with aretention time of 31 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.70 (d, J=7.2 Hz, 3H), 2.10-2.16 (m, 2H), 2.23(m, 3H), 2.90-2.94 (m, 2H), 3.85 (s, 3H), 4.22-4.30 (m, 3H), 6.93-7.06(m, 5H), 7.24 (s, 1H), 7.35-7.38 (m, 2H), 7.66 (s, 1H), 7.71 (s, 1H).

Examples 310 and 311 Synthesis of (+) and(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

457 mg of the racemic title compound was obtained from1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (467 mg) and(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (500mg) by the same method as in Examples 194 and 195. The racemic titlecompound (457 mg) was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1)to obtain the title optically active compound with positive opticalrotation and a retention time of 12 minutes (209 mg) and the titleoptically active compound with negative optical rotation and a retentiontime of 18 minutes (206 mg).

The property values of the title optically active compound with aretention time of 12 minutes are as follows.

ESI-MS; m/z 480 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.89-2.00 (m, 1H),2.08-2.35 (m, 2H), 2.29 (d, J=0.8 Hz, 3H), 2.40-2.52 (m, 1H), 3.84 (s,3H), 4.27-4.40 (m, 2H), 4.70 (dd, J=6.4, 8.8 Hz, 1H), 6.89-6.92 (m, 1H),7.01-7.08 (m, 2H), 7.11-7.16 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.40 (dd,J=7.6, 7.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.69 (d, J=1.2 Hz, 1H), 7.73 (d,J=8.0 Hz, 1H).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

ESI-MS; m/z 480 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.89-2.00 (m, 1H),2.08-2.35 (m, 2H), 2.29 (d, J=0.8 Hz, 3H), 2.40-2.52 (m, 1H), 3.84 (s,3H), 4.27-4.40 (m, 2H), 4.70 (dd, J=6.4, 8.8 Hz, 1H), 6.89-6.92 (m, 1H),7.01-7.08 (m, 2H), 7.11-7.16 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.40 (dd,J=7.6, 7.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.69 (d, J=1.2 Hz, 1H), 7.73 (d,J=8.0 Hz, 1H).

Examples 312 and 313 Synthesis of (+) and(−)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

292 mg of the racemic title compound was obtained from1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (514 mg) and(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylicacid (500 mg) by the same method as in Examples 194 and 195. The racemictitle compound (18 mg) was separated by CHIRALPAK™ IB manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase:hexane:ethanol=1:1) to obtain the title optically active compound withpositive optical rotation and a retention time of 17 minutes (6 mg) andthe title optically active compound with negative optical rotation and aretention time of 32 minutes (6 mg).

The property value of the title optically active compound with aretention time of 17 minutes is as follows.

ESI-MS; m/z 498 [M⁺+H].

The property values of the title optically active compound with aretention time of 32 minutes are as follows.

ESI-MS; m/z 498 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.89-2.02 (m, 1H),2.10-2.34 (m, 2H), 2.29 (s, 3H), 2.40-2.52 (m, 1H), 3.82 (s, 3H),4.28-4.41 (m, 2H), 4.69 (dd, J=6.0, 8.0 Hz, 1H), 6.91 (s, 1H), 6.97-7.06(m, 2H), 7.09-7.20 (m, 2H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.49 (dd,J=7.6, 7.6 Hz, 1H), 7.58 (d, J=16.4 Hz, 1H), 7.69-7.78 (m, 2H).

Examples 314 and 315 Synthesis of (+) and(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol

123 mg of the racemic title compound was obtained by the same method asin Examples 53 and 54 from the optically active compound synthesized bythe method in Examples 310 and 311 with positive optical rotation and aretention time of 12 minutes,2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(183 mg). The racemic title compound (123 mg) was separated byCHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=1:1) to obtain the title opticallyactive compound with positive optical rotation and a retention time of13 minutes (47 mg) and the title optically active compound with negativeoptical rotation and a retention time of 21 minutes (48 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

ESI-MS; m/z 496 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.13 (m, 1H), 2.29(d, J=0.8 Hz, 3H), 2.25-2.58 (m, 3H), 3.80 (s, 3H), 4.12-4.24 (m, 1H),4.30-4.40 (m, 1H), 4.74 (brs, 1H), 6.85-6.90 (m, 1H), 6.95-7.07 (m, 3H),7.15 (d, J=8.0 Hz, 1H), 7.40 (d, J=16.4 Hz, 1H), 7.46 (dd, J=7.6, 7.6Hz, 1H), 7.58 (dd, J=7.6, 7.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (d,J=8.0 Hz, 1H), 7.79 (brs, 1H).

The property values of the title optically active compound with aretention time of 21 minutes are as follows.

ESI-MS; m/z 496 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.02-2.13 (m, 1H), 2.29(d, J=0.8 Hz, 3H), 2.25-2.58 (m, 3H), 3.80 (s, 3H), 4.12-4.24 (m, 1H),4.30-4.40 (m, 1H), 4.74 (brs, 1H), 6.85-6.90 (m, 1H), 6.95-7.07 (m, 3H),7.15 (d, J=8.0 Hz, 1H), 7.40 (d, J=16.4 Hz, 1H), 7.46 (dd, J=7.6, 7.6Hz, 1H), 7.58 (dd, J=7.6, 7.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (d,J=8.0 Hz, 1H), 7.79 (brs, 1H).

Examples 316 and 317 Synthesis of (+) and(−)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

254 mg of the title compound as a racemate was obtained from ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidatedihydrochloride (1.20 g) and 4-chloro-2-(2-trifluoromethylphenyl)butyricacid hydrazide hydrochloride (1.25 g) by the same method as in Examples140 and 141. The racemic title compound (254 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=4:1) to obtain the title opticallyactive compound with positive optical rotation and a retention time of28 minutes (55 mg) and the title optically active compound with negativeoptical rotation and a retention time of 48 minutes (40 mg).

The property value of the title optically active compound with aretention time of 28 minutes is as follows.

ESI-MS; m/z 466 [M⁺+H].

The property value of the title optically active compound with aretention time of 48 minutes is as follows.

ESI-MS; m/z 466 [M⁺+H].

Examples 318 and 319 Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-o-tolylpiperidin-2-one

339 mg of the title compound was obtained using o-tolylacetic acid (1 g)as a starting material according to the method in Examples 20 and 21.The property values of the compound are as follows.

ESI-MS; m/z 205 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 1.70-2.20 (m, 4H), 3.33 (s, 3H), 3.40-3.98 (m,3H), 4.63 (brs, 2H), 6.66-7.38 (m, 4H).

Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

175.7 mg of a racemate of the title compound was obtained using1-amino-3-o-tolylpiperidin-2-one (339 mg) as a starting materialaccording to the method in Examples 168 and 169. The resulting racemate(100 mg) was separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain a(+)-isomer of the title optically active compound with a retention timeof 12 minutes (42.6 mg; 99% ee) and a (−)-isomer of the title opticallyactive compound with a retention time of 25 minutes (44.7 mg; 99% ee).

The property values of the title optically active compound with aretention time of 12 minutes are as follows.

ESI-MS; m/z 427 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 1.76-2.52 (m, 10H), 4.04 (s, 3H), 4.21-4.40 (m,2H), 4.55 (t, J=6.0 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.88-7.01 (m, 2H),7.06-7.32 (m, 3H), 7.40-7.51 (m, 2H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (d,J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 25 minutes are as follows.

ESI-MS; m/z 427 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 1.76-2.52 (m, 10H), 4.04 (s, 3H), 4.21-4.40 (m,2H), 4.55 (t, J=6.0 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.88-7.01 (m, 2H),7.06-7.32 (m, 3H), 7.40-7.51 (m, 2H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (d,J=1.2 Hz, 1H).

Examples 320 and 321 Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(3-trifluoromethylphenyl)piperidin-2-one

282.7 mg of the title compound was obtained using methyl3-(trifluoromethyl)phenylacetate (1 g) as a starting material accordingto the method in Examples 20 and 21. The property value of the compoundis as follows.

ESI-MS; m/z 259 [M⁺+H].

Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

60.7 mg of a racemate of the title compound was obtained using1-amino-3-(3-trifluoromethylphenyl)piperidin-2-one (282.7 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (60.7 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase:hexane:ethanol=1:1) to obtain a (+)-isomer of the title optically activecompound with a retention time of 16 minutes (20 mg; >99% ee) and a(−)-isomer of the title optically active compound with a retention timeof 52 minutes (19.1 mg; >99% ee).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 481 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.48 (m, 7H), 4.05 (s, 3H), 4.26-4.45 (m,3H), 6.91-6.99 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.41-7.52 (m, 4H), 7.56(d, J=8.0 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.78 (brs, 1H).

The property values of the title optically active compound with aretention time of 52 minutes are as follows.

ESI-MS; m/z 481 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 1.98-2.48 (m, 7H), 4.05 (s, 3H), 4.26-4.45 (m,3H), 6.91-6.99 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.41-7.52 (m, 4H), 7.56(d, J=8.0 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.78 (brs, 1H).

Examples 322 and 323 Synthesis of[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methanoland[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methanol

Synthesis of 5-chloro-2-(2-hydroxymethylphenyl)pentanoic acid hydrazide

1.29 g of the title compound was obtained using 3-isochromanone (25 g)as a starting material according to the method in Examples 1 and 2. Theproperty value of the compound is as follows.

ESI-MS; m/z 257 [M⁺+H].

Synthesis of[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methanoland[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methanol

4.4 mg of a racemate of the title compound was obtained using5-chloro-2-(2-hydroxymethylphenyl)pentanoic acid hydrazide (388 mg) as astarting material according to the method in Examples 1 and 2. Theresulting racemate (4.4 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol)to obtain a (+)-isomer of the title optically active compound with aretention time of 11 minutes (0.91 mg; >99% ee) and a (−)-isomer of thetitle optically active compound with a retention time of 17 minutes(0.89 mg; >99% ee).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

ESI-MS; m/z 443 [M⁺+H].

¹H-NMR (acetone-d6) δ (ppm): 1.80-2.50 (m, 7H), 4.07 (s, 3H), 4.27-4.38(m, 2H), 4.52-4.88 (m, 3H), 7.02-7.10 (m, 1H), 7.14-7.38 (m, 5H),7.46-7.59 (m, 2H), 7.77 (d, J=7.6 Hz, 1H), 7.87 (brs, 1H).

The property values of the title optically active compound with aretention time of 17 minutes are as follows.

ESI-MS; m/z 443 [M⁺+H].

¹H-NMR (acetone-d6) δ (ppm): 1.80-2.50 (m, 7H), 4.07 (s, 3H), 4.27-4.38(m, 2H), 4.52-4.88 (m, 3H), 7.02-7.10 (m, 1H), 7.14-7.38 (m, 5H),7.46-7.59 (m, 2H), 7.77 (d, J=7.6 Hz, 1H), 7.87 (brs, 1H).

Examples 324 and 325 Synthesis of (+) and(−)-8-(2-fluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

{2-{2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}methanol(350 mg) was dissolved in dichloromethane (40 mL). This was addeddropwise to a solution of DAST (1.04 mL) in dichloromethane (6 mL)cooled to −78° C., and the reaction solution was stirred for one hour.Saturated sodium bicarbonate water was added to the reaction solution,followed by extraction with dichloromethane. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography (carrier: NHsilica, elution solvent: ethyl acetate:methanol=9:1) to obtain aracemate of the title compound (70 mg). The resulting racemate wasseparated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtainthe title optically active compound with a retention time of 7 minutesand positive optical rotation (20 mg) and the title optically activecompound with a retention time of 9 minutes and negative opticalrotation (20 mg), where the retention time is an analysis result inCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (Lot.IB00CD-FD026, mobile phase: ethanol, flow rate: 0.5 mL/min).

The property values of the title optically active compound with aretention time of 7 minutes under the analysis conditions are asfollows.

ESI-MS; m/z 455 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.99-2.16 (m, 2H),2.23-2.30 (m, 4H), 2.42 (m, 1H), 4.04 (s, 3H), 4.33 (m, 2H), 4.58 (m,1H), 5.48 (dd, J=10.8, 108.8 Hz, 1H), 5.60 (m, 1H) 6.92-6.95 (m, 3H),7.30-7.47 (m, 5H), 7.65 (d, J=15.6 Hz, 1H), 7.79 (m, 1H).

The property values of the title optically active compound with aretention time of 9 minutes under the analysis conditions are asfollows.

ESI-MS; m/z 455 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.99-2.16 (m, 2H),2.23-2.30 (m, 4H), 2.42 (m, 1H), 4.04 (s, 3H), 4.33 (m, 2H), 4.58 (m,1H), 5.48 (dd, J=10.8, 108.8 Hz, 1H), 5.60 (m, 1H) 6.92-6.95 (m, 3H),7.30-7.47 (m, 5H), 7.65 (d, J=15.6 Hz, 1H), 7.79 (m, 1H).

Examples 326 and 327 Synthesis of (+) and(−)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(2-fluorophenyl)piperidin-2-one

1.12 g of the title compound was obtained using 2-fluorophenylaceticacid (3.0 g) as a starting material according to the method in Examples20 and 21. The property value of the compound is as follows.

ESI-MS; m/z 209 [M⁺+H].

Synthesis of (+) and(−)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (21 mg) was obtained using1-amino-3-(2-fluorophenyl)piperidin-2-one (300 mg) as a startingmaterial according to the method in Examples 168 and 169. The resultingracemate (219 mg) was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate:10 mL/min) to obtain the title optically active compound with aretention time of 11.4 minutes and positive optical rotation (90 mg) andthe title optically active compound with a retention time of 19 minutesand negative optical rotation (90 mg).

The property values of the title optically active compound with aretention time of 11.4 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.27 (m, 2H), 2.29 (s, 3H), 2.34-2.42 (m,1H), 4.05 (s, 3H), 4.28-4.34 (m, 2H), 4.61 (dd, J=7.0, 7.0 Hz, 1H), 6.93(d, J=9.4 Hz, 1H), 6.92-6.98 (m, 1H), 7.06-7.12 (m, 2H), 7.46 (d, J=15.6Hz, 1H), 7.47 (d, J=9.4 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2Hz, 1H).

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.27 (m, 2H), 2.29 (s, 3H), 2.34-2.42 (m,1H), 4.05 (s, 3H), 4.28-4.34 (m, 2H), 4.61 (dd, J=7.0, 7.0 Hz, 1H), 6.93(d, J=9.4 Hz, 1H), 6.92-6.98 (m, 1H), 7.06-7.12 (m, 2H), 7.46 (d, J=15.6Hz, 1H), 7.47 (d, J=9.4 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2Hz, 1H).

Examples 328 and 329 Synthesis of(+)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(5-fluoro-2-trifluoromethylphenyl)piperidin-2-one

890 mg of the title compound was obtained using5-fluoro-2-trifluoromethylphenylacetic acid (1 g) as a starting materialaccording to the method in Examples 194 and 195. The property value ofthe compound is as follows.

ESI-MS; m/z 277 [M⁺+H].

Synthesis of(+)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (132 mg) was obtained using(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acidtrifluoroacetate (353 mg) and1-amino-3-(5-fluoro-2-trifluoromethylphenyl)piperidin-2-one (200 mg) asstarting materials according to the method in Examples 168 and 169. Theresulting racemate (132 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase;hexane:ethanol=7:3, flow rate: 11 mL/min) to obtain the title opticallyactive compound with a retention time of 18 minutes and positive opticalrotation (46 mg), and the title optically active compound with aretention time of 31 minutes and negative optical rotation (45 mg).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.87-2.00 (m, 1H), 2.10-2.33 (m, 2H), 2.28 (s,3H), 2.42-2.52 (m, 1H), 4.03 (s, 3H), 4.27-4.42 (m, 2H), 4.68 (dd,J=8.4, 6.4 Hz, 1H), 6.73 (dd, J=9.2, 2.4 Hz, 1H), 6.93 (d, J=7.6 Hz,1H), 6.95 (d, J=1.2 Hz, 1H), 7.08 (ddd, J=8.8, 8.0, 2.4 Hz, 1H), 7.43(d, J=15.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H),7.73 (dd, J=8.8, 5.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 31 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.87-2.00 (m, 1H), 2.10-2.33 (m, 2H), 2.28 (s,3H), 2.42-2.52 (m, 1H), 4.03 (s, 3H), 4.27-4.42 (m, 2H), 4.68 (dd,J=8.4, 6.4 Hz, 1H), 6.73 (dd, J=9.2, 2.4 Hz, 1H), 6.93 (d, J=7.6 Hz,1H), 6.95 (d, J=1.2 Hz, 1H), 7.08 (ddd, J=8.8, 8.0, 2.4 Hz, 1H), 7.43(d, J=15.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H),7.73 (dd, J=8.8, 5.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

Examples 330 and 331 Synthesis of(+)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-(6-fluoro-2-trifluoromethylphenyl)piperidin-2-one

381 mg of the title compound was obtained using6-fluoro-2-trifluoromethylphenylacetic acid (1 g) as a starting materialaccording to the method in Examples 20 and 21. The property value of thecompound is as follows.

ESI-MS; m/z 277 [M⁺+H].

Synthesis of(+)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridineand(−)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (181 mg) was obtained using(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid(340 mg) and 1-amino-3-(6-fluoro-2-trifluoromethylphenyl)piperidin-2-one(200 mg) as starting materials according to the method in Examples 168and 169. The resulting racemate (181 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: hexane:ethanol=7:3, flow rate: 12 mL/min) to obtain the titleoptically active compound with a retention time of 18 minutes andpositive optical rotation (76 mg) and the title optically activecompound with a retention time of 34 minutes and negative opticalrotation (75 mg).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.07-2.41 (m, 7H), 4.01 (s, 3H), 4.19-4.26 (m,1H), 4.39-4.43 (m, 1H), 4.52-4.56 (m, 1H), 6.91 (d, J=6.9 Hz, 1H), 6.94(s, 1H), 7.22 (t, J=8.8 Hz, 1H), 7.37-7.45 (m, 3H), 7.55 (d, J=7.6 Hz,1H), 7.60 (d, J=15.6 Hz, 1H) 7.75 (s, 1H).

The property values of the title optically active compound with aretention time of 34 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.07-2.41 (m, 7H), 4.01 (s, 3H), 4.19-4.26 (m,1H), 4.39-4.43 (m, 1H), 4.52-4.56 (m, 1H), 6.91 (d, J=6.9 Hz, 1H), 6.94(s, 1H), 7.22 (t, J=8.8 Hz, 1H), 7.37-7.45 (m, 3H), 7.55 (d, J=7.6 Hz,1H), 7.60 (d, J=15.6 Hz, 1H) 7.75 (s, 1H).

Examples 332 and 333 Synthesis of (+) and(−)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (21 mg) was obtained using1-amino-3-(3-fluoro-2-methylphenyl)piperidin-2-one (197 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (21 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol,flow rate: 10 mL/min) to obtain the title optically active compound witha retention time of 12.5 minutes and positive optical rotation (8 mg)and the title optically active compound with a retention time of 27minutes and negative optical rotation (8 mg).

The property values of the title optically active compound with aretention time of 12.5 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.27 (m, 3H), 2.28-2.38 (m, 1H), 2.29 (s,3H), 2.30 (s, 3H) 4.04 (s, 3H), 4.24-4.38 (m, 2H), 4.53-4.60 (m, 1H),6.53 (d, J=7.7 Hz, 1H), 6.91-6.98 (m, 2H), 6.93 (d, J=7.7 Hz, 1H),7.05-7.12 (m, 1H) 7.46 (d, J=15.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.65(d, J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H).

The property values of the title optically active compound with aretention time of 27 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.27 (m, 3H), 2.28-2.38 (m, 1H), 2.29 (s,3H), 2.30 (s, 3H) 4.04 (s, 3H), 4.24-4.38 (m, 2H), 4.53-4.60 (m, 1H),6.53 (d, J=7.7 Hz, 1H), 6.91-6.98 (m, 2H), 6.93 (d, J=7.7 Hz, 1H),7.05-7.12 (m, 1H) 7.46 (d, J=15.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.65(d, J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H).

Examples 334 and 335 Synthesis of (+) and(−)-8-(4-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 2-(4-fluoro-3-methylphenyl)acetamide

4-Fluoro-3-methylphenylacetonitrile (1.1 g) was dissolved in toluene (35ml), and trimethylsiloxypotassium (3.7 g) was added. After stirring at110° C. for 2.5 hours, saturated sodium bicarbonate water was added,followed by separation with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure to obtain 863 mg of the title compound. The property values ofthe compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.27 (s, 3H), 3.52 (s, 2H), 5.24-5.60 (m, 1H),6.92-7.15 (m, 3H).

Synthesis of ethyl 2-(4-fluoro-3-methylphenyl)acetate

2-(4-Fluoro-3-methylphenyl)acetamide (863 mg) was dissolved in saturatedhydrochloric acid/ethanol (20 ml), and the reaction solution was stirredat 85° C. for 10 hours. The reaction solution was concentrated underreduced pressure and then diluted with ethyl acetate, followed byseparation with water. The organic layer was washed with saturatedaqueous sodium bicarbonate and brine and then dried over magnesiumsulfate. 919 mg of the title compound was obtained by concentrationunder reduced pressure. The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.25 (t, J=8.4 Hz, 3H), 2.05 (s, 3H), 2.26 (s,3H) 3.54 (s, 2H), 4.15 (q, J=8.4 Hz, 1H), 6.92-6.97 (m, 1H), 7.03-7.10(m, 2H).

Synthesis of 1-amino-3-(4-fluoro-3-methylphenyl)piperidin-2-one

396 mg of the title compound was obtained using ethyl2-(4-fluoro-3-methylphenyl)acetate (919 mg) as a starting materialaccording to the method in Examples 20 and 21. The property value of thecompound is as follows.

ESI-MS; m/z 223 [M⁺+H].

Synthesis of (+) and(−)-8-(4-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (44.5 mg) was obtained using1-amino-3-(4-fluoro-3-methylphenyl)piperidin-2-one (135 mg) as astarting material according to the method in Examples 168 and 169. Theresulting racemate (44.5 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol,flow rate: 10 mL/min) to obtain the title optically active compound witha retention time of 12.5 minutes and positive optical rotation (20 mg)and the title optically active compound with a retention time of 19minutes and negative optical rotation (20 mg).

The property values of the title optically active compound with aretention time of 12.5 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.80-1.98 (m, 1H), 1.98-2.14 (m, 1H), 2.25 (s,3H), 2.26-2.40 (m, 2H), 2.29 (s, 3H), 4.05 (s, 3H), 4.21-4.36 (m, 3H),6.88-7.00 (m, 5H), 7.46 (d, J=7.7 Hz, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.65(d, J=15.7 Hz, 1H), 7.75-7.78 (m, 1H).

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.80-1.98 (m, 1H), 1.98-2.14 (m, 1H), 2.25 (s,3H), 2.26-2.40 (m, 2H), 2.29 (s, 3H), 4.05 (s, 3H), 4.21-4.36 (m, 3H),6.88-7.00 (m, 5H), 7.46 (d, J=7.7 Hz, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.65(d, J=15.7 Hz, 1H), 7.75-7.78 (m, 1H).

Examples 336 and 337 Synthesis of (+) and(−)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acidditrifluoroacetate (800 mg) and1-amino-3-(3,5-difluorophenyl)piperidin-2-one (445 mg) according to themethod in Examples 168 and 169. The resulting racemate was separated byCHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm; mobile phase: ethanol) to obtain the title optically activecompound with a retention time of 6.1 minutes and positive opticalrotation (35.6 mg, >99% ee) and the title optically active compound witha retention time of 8.1 minutes and negative optical rotation (40.6mg, >99% ee).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 449 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.00-2.25 (m, 3H), 2.30(s, 3H), 2.35-2.40 (m, 1H), 4.06 (s, 3H), 4.28-4.35 (m, 3H), 6.67-6.77(m, 3H), 6.95 (d, J=8.0 Hz, 1H), 6.97 (s, 1H), 7.46 (d, J=8.0 Hz, 1H),7.47 (d, J=16.0 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.78 (s, 1H).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 449 [M⁺+H]. 1H-NMR (CDCl₃) δ (ppm): 2.00-2.25 (m, 3H), 2.30(s, 3H), 2.35-2.40 (m, 1H), 4.06 (s, 3H), 4.28-4.35 (m, 3H), 6.67-6.77(m, 3H), 6.95 (d, J=8.0 Hz, 1H), 6.97 (s, 1H), 7.46 (d, J=8.0 Hz, 1H),7.47 (d, J=16.0 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.78 (s, 1H).

Examples 338 and 339 Synthesis of (R) and(S)-2-{(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2,3,4-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-a]pyridine

Synthesis of 1-amino-3-(2,3,4-trifluorophenyl)piperidin-2-one

The title compound (220 mg) was obtained from2,3,4-trifluorophenylacetic acid (1.48 g) by the same method as inExamples 1 and 2. The property values of the compound are as follows.

ESI-MS; m/z 245 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.90-2.04 (m, 3H),2.11-2.17 (m, 1H), 3.56-3.70 (m, 2H), 3.81-3.86 (m, 1H), 4.58 (brs, 2H),6.82-6.96 (m, 2H).

Synthesis of (R) and(S)-2-{(E)-3-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]vinyl}-8-(2,3,4-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-a]pyridine

The racemic title compound (100 mg) was obtained from1-amino-3-(2,3,4-trifluorophenyl)piperidin-2-one (220 mg) by the samemethod as in Examples 168 and 169. The resulting racemic title compound(100 mg) was separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3) toobtain the title optically active compound with positive opticalrotation and a retention time of 53 minutes (19.5 mg) and the titleoptically active compound with negative optical rotation and a retentiontime of 90 minutes (13.5 mg). The property values of the compound are asfollows. The title optically active compound with a retention time of 53minutes

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.99-2.08 (m, 1H),2.09-2.25 (m, 2H), 2.29 (s, 3H), 2.35-2.43 (m, 1H), 4.05 (s, 3H),4.25-4.35 (m, 2H), 4.53-4.57 (m, 1H), 6.68-6.74 (m, 1H), 6.90-6.96 (m,3H), 7.44 (d, J=16.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=16.0Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The title optically active compound with a retention time of 90 minutes

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.99-2.08 (m, 1H),2.09-2.25 (m, 2H), 2.29 (s, 3H), 2.35-2.43 (m, 1H), 4.05 (s, 3H),4.25-4.35 (m, 2H), 4.53-4.57 (m, 1H), 6.68-6.74 (m, 1H), 6.90-6.96 (m,3H), 7.44 (d, J=16.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=16.0Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

Examples 340 and 341 Synthesis of (+) and(−)-8-benzo[1,3]dioxol-4-yl-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 1-amino-3-benzo[1,3]dioxol-4-yl-piperidin-2-one

1.19 g of the title compound was obtained usingbenzo[1,3]dioxol-4-carbaldehyde (5.0 g) as a starting material accordingto the method in Examples 293 and 294. The property value of thecompound is as follows.

ESI-MS; m/z 235 [M⁺+H].

Synthesis of (+) and(−)-8-benzo[1,3]dioxol-4-yl-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (810 mg) was obtained using1-amino-3-benzo[1,3]dioxol-4-yl-piperidin-2-one (1.19 g) as a startingmaterial according to the method in Examples 168 and 169. The resultingracemate (100 mg) was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate:10 mL/min) to obtain the title optically active compound with aretention time of 14.6 minutes and positive optical rotation (40 mg) andthe title optically active compound with a retention time of 21 minutesand negative optical rotation (40 mg).

The property values of the title optically active compound with aretention time of 14.6 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.28 (m, 3H), 2.28-2.38 (m, 1H), 2.29 (s,3H), 4.05 (s, 3H), 4.24-4.32 (m, 2H), 4.44 (dd, J=6.6, 5.6 Hz, 1H), 5.92(s, 2H), 6.50 (dd, J=7.0, 1.6 Hz, 1H), 6.74-6.82 (m, 2H), 6.93 (d, J=7.8Hz, 1H), 6.95-6.97 (m, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.48 (d, J=15.6 Hz,1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 21 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.28 (m, 3H), 2.28-2.38 (m, 1H), 2.29 (s,3H), 4.05 (s, 3H), 4.24-4.32 (m, 2H), 4.44 (dd, J=6.6, 5.6 Hz, 1H), 5.92(s, 2H), 6.50 (dd, J=7.0, 1.6 Hz, 1H), 6.74-6.82 (m, 2H), 6.93 (d, J=7.8Hz, 1H), 6.95-6.97 (m, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.48 (d, J=15.6 Hz,1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).

Examples 342 and 343 Synthesis of (+) and(−)-8-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 5-chloro-2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)valeric acidhydrazide

580 mg of the title compound was obtained using2,2-difluoro-benzo[1,3]dioxol-4-carbaldehyde (1.8 g) as a startingmaterial according to the method in Examples 293 and 294. The propertyvalue of the compound is as follows.

ESI-MS; m/z 307 [M⁺+H].

Synthesis of (+) and(−)-8-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (280 mg) was obtained using5-chloro-2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)valeric acid hydrazide(555 mg) and ethyl(E)-3-[6-methoxy-5-(4-methylimidazol-1-yl)-pyridin-2-yl]acrylimidate(482 mg) as starting materials according to the method in Examples 1 and2. The resulting racemate (280 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobilephase: ethanol, flow rate: 10 mL/min) to obtain the title opticallyactive compound with a retention time of 13 minutes and positive opticalrotation (110 mg) and the title optically active compound with aretention time of 18 minutes and negative optical rotation (120 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.07-2.28 (m, 3H), 2.30 (s, 3H), 2.38-2.47 (m,1H), 4.05 (s, 3H), 4.29-4.34 (m, 2H), 4.54 (dd, J=6.6, 5.8 Hz, 1H), 6.74(dd, J=7.8, 1.4 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.95-6.97 (m, 1H),6.98-7.06 (m, 2H), 7.46 (d, J=15.7 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.67(d, J=15.7 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 21 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.07-2.28 (m, 3H), 2.30 (s, 3H), 2.38-2.47 (m,1H), 4.05 (s, 3H), 4.29-4.34 (m, 2H), 4.54 (dd, J=6.6, 5.8 Hz, 1H), 6.74(dd, J=7.8, 1.4 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.95-6.97 (m, 1H),6.98-7.06 (m, 2H), 7.46 (d, J=15.7 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.67(d, J=15.7 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

Example 344 Synthesis of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[(S)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol

Reaction was carried out using1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (2.0 g) as a startingmaterial, and the resulting crude product was purified by silica gelcolumn chromatography (amino silica, 40 μm, 53 g, ethylacetate:heptane=0:1 to 1:0) to obtain8-(2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(739 mg) and a racemate of the title compound (88 mg) according to themethod in Examples 194 and 195. The property values of the compound areas follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.00 (m, 1H), 2.10-2.23 (m, 1H), 2.23-2.30(m, 1H), 2.28 (s, 3H), 2.40-2.51 (m, 1H) 4.30-4.42 (m, 2H), 4.68 (dd,J=8.8, 5.6 Hz, 1H), 6.34 (d, J=7.8 Hz, 1H), 7.00 (d, J=7.4 Hz, 1H),7.13-7.23 (m, 3H), 7.37-7.42 (m, 2H), 7.46-7.52 (m, 1H), 7.73 (d, J=7.4Hz, 1H), 8.14 (d, J=1.2 Hz, 1H).

Examples 345 and 346 Synthesis of (+) and(−)-2-{(E)-2-[6-chloro-5-(4-methyl-1H-imidazol-1-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol(500 mg) in phosphorus oxychloride (10 ml) was heated and stirred at100° C. overnight. The reaction solution was concentrated under reducedpressure. Ethyl acetate and a saturated sodium bicarbonate solution wereadded and the organic layer was separated. The resulting organic layerwas washed with brine and then dried over anhydrous sodium sulfate. Thedrying agent was separated by filtration, and then the organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to obtain a racemate of the title compound(176 mg). The resulting racemate was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=7:3) to obtain the title optically active compoundwith positive optical rotation (46 mg, >99% ee) and the title opticallyactive compound with negative optical rotation (47 mg, >99% ee).

The property values of the title optically active compound with positiveoptical rotation are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.00 (m, 1H), 2.07-2.22 (m, 1H), 2.22-2.32(m, 1H), 2.31 (s, 3H), 2.42-2.50 (m, 1H), 4.29-4.41 (m, 2H), 4.69 (dd,J=8.8, 6.0 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.30(d, J=7.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.45-7.51 (m, 2H), 7.56 (d,J=8.0 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.73 (d,J=7.6 Hz, 1H).

The property values of the title optically active compound with negativeoptical rotation are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.00 (m, 1H), 2.07-2.22 (m, 1H), 2.22-2.32(m, 1H), 2.31 (s, 3H), 2.42-2.50 (m, 1H), 4.29-4.41 (m, 2H), 4.69 (dd,J=8.8, 6.0 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.30(d, J=7.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.45-7.51 (m, 2H), 7.56 (d,J=8.0 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.73 (d,J=7.6 Hz, 1H).

Examples 347 and 348 Synthesis of (+) and(−)-2-{(E)-2-[6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Synthesis ofN-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]-3-p-tolylsulfanylpropionamide

EDC (9.01 g), HOBT (6.34 g) and IPEA (21.8 ml) were added to a solutionof 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (8.08 g) and3-[(4-methylphenyl)thio]propionic acid (7.37 g) in DMF (80 ml) undercooling in an ice water bath. The reaction solution was stirred at roomtemperature for four hours. Ethyl acetate and a sodium bicarbonatesolution were added to the reaction solution, and the organic layer wasseparated. The resulting organic layer was washed with brine and thendried over anhydrous sodium sulfate. The drying agent was separated byfiltration, and then the organic layer was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain the title compound (13.51 g). The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.12 (m, 3H), 2.20-2.28 (m, 1H), 2.32 (s,3H), 2.44-2.58 (m, 2H), 3.12-3.24 (m, 2H), 3.58-3.64 (m, 1H), 3.84-3.92(m, 1H), 4.08-4.14 (m, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz,2H), 7.34 (dd, J=8.0, 7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.53 (dd,J=8.0, 7.6 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.79 (brs, 1H).

Synthesis of2-(2-p-tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

A solution ofN-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]-3-p-tolylsulfanylpropionamidein phosphorus oxychloride (80 ml) was heated and stirred at 120° C. forone hour. The reaction solution was concentrated under reduced pressure,followed by addition of acetic acid (100 ml) and sodium acetate (23.8 g)heated and dried under reduced pressure. The reaction solution washeated and stirred at 150° C. for 1.5 hours. After leaving to cool, thereaction solution was concentrated under reduced pressure. Ethyl acetateand a saturated sodium bicarbonate solution were added and the organiclayer was separated. The resulting organic layer was washed with brineand then dried over anhydrous sodium sulfate. The drying agent wasseparated by filtration, and then the organic layer was concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography to obtain the title compound (8.8 g). The property valuesof the compound are as follows.

ESI-MS; m/z 419 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.80-1.92 (m, 1H),2.04-2.15 (m, 1H), 2.15-2.27 (m, 1H), 2.30 (s, 3H), 2.36-2.45 (m, 1H),2.95-3.00 (m, 2H), 3.18-3.23 (m, 2H), 4.18-4.30 (m, 2H), 7.56 (dd,J=8.6, 6.2 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 7.27(d, J=8.0 Hz, 2H), 7.35 (dd, J=8.0, 7.6 Hz, 1H), 7.45 (dd, J=8.0, 7.6Hz, 1H), 7.68 (d, J=8.0 Hz, 1H).

Synthesis of2-[2-(toluene-4-sulfinyl)ethyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

2-(2-p-Tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(8.8 g) was dissolved in a mixed solvent of methanol-water (2:1 v/v)(300 ml). Sodium periodide (6.78 g) was added under cooling with an icewater bath, and the reaction solution was stirred at room temperatureovernight. Ethyl acetate and water were added to the reaction solution,and the organic layer was separated. The resulting organic layer waswashed with brine and then dried over anhydrous sodium sulfate. Thedrying agent was separated by filtration and the organic layer wasconcentrated under reduced pressure to obtain the title compound (8.87g). The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.80-1.93 (m, 1H), 2.02-2.15 (m, 1H), 2.16-2.28(m, 1H), 2.36-2.45 (m, 1H), 2.39 (s, 3H), 2.83-2.98 (m, 1H), 3.05-3.30(m, 3H), 4.17-4.30 (m, 2H), 4.54-4.60 (m, 1H), 6.93 (d, J=7.6 Hz, 1H),7.26-7.32 (m, 2H), 7.36 (dd, J=8.0, 7.6 Hz, 1H), 7.43-7.52 (m, 3H), 7.69(d, J=7.6 Hz, 1H).

Synthesis of8-(2-trifluoromethylphenyl)-2-vinyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

2-[2-(Toluene-4-sulfinyl)ethyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(8.87 g) was dissolved in toluene (300 ml), and the reaction solutionwas heated under reflux for three days. After leaving to cool, thereaction solution was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to obtain the titlecompound (4.27 g). The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.87-1.97 (m, 1H), 2.08-2.16 (m, 1H), 2.18-2.28(m, 1H), 2.38-2.48 (m, 1H), 4.22-4.34 (m, 2H), 4.66 (dd, J=8.2, 1.8 Hz,1H), 5.43 (dd, J=11.2, 1.4 Hz, 1H), 6.13 (dd, J=17.6, 1.4 Hz, 1H), 6.65(dd, J=17.6, 11.2 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.0, 7.2Hz, 1H), 7.46 (dd, J=7.6, 7.2 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H).

Synthesis of 2,6-difluoro-3-nitropyridine

Tetramethylammonium nitride (4.5 g) was suspended in dichloromethane (10ml), and a solution of trifluoromethanesulfonic anhydride (5.56 ml) indichloromethane (5 ml) was added dropwise at room temperature. Afterstirring at room temperature for 1.5 hours, a solution of2,6-difluoropyridine (2 ml) in dichloromethane (5 ml) was added at roomtemperature, and the reaction solution was heated under refluxovernight. After leaving to cool, the reaction solution was poured intoan ice-cooled saturated sodium bicarbonate solution. Dichloromethane wasadded and the organic layer was separated. The resulting organic layerwas washed with brine and then dried over anhydrous sodium sulfate. Thedrying agent was separated by filtration and the organic layer wasconcentrated under reduced pressure to obtain the title compound (3.84g). The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 7.03-7.07 (m, 1H), 8.66-8.73 (m, 1H).

Synthesis of 2,6-difluoro-3-aminopyridine

2,6-Difluoro-3-nitropyridine (3.84 g) was dissolved in ethanol (42 ml).A solution of iron powder (4.03 g) and ammonium chloride (2.57 g) inwater (14 ml) was added, and the reaction solution was heated andstirred at 80° C. for one hour. After leaving to cool, the reactionsolution was filtered through celite. Ethyl acetate and water were addedand the organic layer was separated. The resulting organic layer waswashed with brine and then dried over anhydrous sodium sulfate. Thedrying agent was separated by filtration, and then the organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to obtain the title compound (2.06 g). Theproperty values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 3.66 (brs, 2H), 6.65 (dd, J=8.2, 3.0 Hz, 1H),7.22 (ddd, 10.4, 8.2, 6.8 Hz, 1H).

Synthesis of N-(2,6-difluoropyridin-3-yl)formamide

Acetic anhydride (6 ml) was added to formic acid (6 ml), followed bystirring at room temperature for 20 minutes. Then, a solution of2,6-difluoro-3-aminopyridine (2.06 g) in tert-butyl methyl ether (7 ml)was added so that the reaction solution was maintained at roomtemperature. The reaction solution was further stirred at roomtemperature for four hours. Ethyl acetate and a saturated sodiumbicarbonate solution were added to the reaction solution, and theorganic layer was separated. The resulting organic layer was washed withbrine and then dried over anhydrous sodium sulfate. The drying agent wasseparated by filtration, and then the organic layer was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to obtain the title compound (2.42 g). The propertyvalues of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 6.86 (dd, J=8.8, 2.8 Hz, 1H), 7.42 (brs, 1H),8.49 (s, 1H), 8.83-8.90 (m, 1H).

Synthesis of N-(2,6-difluoropyridin-3-yl)-N-(2-oxopropyl)formamide

Chloroacetone (1.83 ml), cesium carbonate (7.99 g) and potassium iodide(254 mg) were added to a solution ofN-(2,6-difluoropyridin-3-yl)formamide (2.42 g) in N,N-dimethylformamide(50 ml), and the reaction solution was stirred at room temperature fortwo hours. Ethyl acetate and water were added to the reaction solution,and the organic layer was separated. The resulting organic layer waswashed with brine and then dried over anhydrous sodium sulfate. Thedrying agent was separated by filtration, and then the organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to obtain the title compound (2.52 g). Theproperty values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.21 (s, 3H), 4.54 (s, 2H), 6.93 (dd, J=8.0, 3.2Hz, 1H), 7.99 (ddd, J=9.6, 8.4, 7.2 Hz, 1H), 8.28 (s, 1H).

Synthesis of 2,6-difluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine

Trifluoroacetic acid (1.08 ml) and ammonium acetate (1.08 g) were addedto a solution of N-(2,6-difluoropyridin-3-yl)-N-(2-oxopropyl)formamide(2.52 g) in toluene (40 ml), and the reaction solution was heated underreflux in a nitrogen atmosphere for four hours. After leaving to cool,ethyl acetate and a saturated sodium bicarbonate solution were added tothe reaction solution, and the organic layer was separated. Theresulting organic layer was washed with brine and then dried overanhydrous sodium sulfate. The drying agent was separated by filtration,and then the organic layer was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain thetitle compound (2.19 g). The property values of the compound are asfollows.

ESI-MS; m/z 196 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.31 (s, 3H), 6.95-7.00(m, 2H), 7.71-7.72 (m, 1H), 7.90 (ddd, J=9.2, 8.6, 6.8 Hz, 1H).

Synthesis of 2-amino-6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine

28% aqueous ammonia (5 ml) was added to2,6-difluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine (750 mg), and thereaction solution was heated and stirred at 125° C. for one hour using amicrowave synthesizer. Ethyl acetate and water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was washed with brine and then dried over anhydrous sodiumsulfate. The drying agent was separated by filtration and then theorganic layer was concentrated under reduced pressure. The residue waspurified by NH silica gel column chromatography to obtain the titlecompound (92 mg), 6-amino-2-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine(252 mg) and 2,6-diamino-5-(4-methyl-1H-imidazol-1-yl)pyridine (53 mg).

The property values of the title compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.28 (s, 3H), 4.67 (brs, 2H), 6.40 (dd, J=8.2,1.2 Hz, 1H), 6.84 (d, J=1.0 Hz, 1H), 7.49 (dd, J=9.6, 8.2 Hz, 1H), 7.57(d, J=1.0 Hz, 1H).

The property values of6-amino-2-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 4.63 (brs, 2H), 6.352 (dd, J=8.2,3.0 Hz, 1H), 6.79 (d, J=0.8 Hz, 1H), 7.44 (dd, J=8.2, 7.2 Hz, 1H), 7.49(d, J=0.8 Hz, 1H).

The property values of 2,6-diamino-5-(4-methyl-1H-imidazol-1-yl)pyridineare as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.28 (s, 3H), 4.25 (brs, 2H), 4.37 (brs, 2H),5.91 (d, J=8.2 Hz, 1H), 6.73 (d, J=1.4 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H),7.43 (d, J=1.4 Hz, 1H).

Synthesis of 6-bromo-2-fluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine

Copper sulfate pentahydrate (438 mg) and sodium bromide (289 mg) weredissolved in water (8 ml), and a solution sodium sulfite (176 mg) inwater (6 ml) was added dropwise at room temperature. After stirring atroom temperature for 15 minutes, the supernatant was removed and theresulting precipitate was washed with water. A 24% hydrobromic acidsolution (5 ml) was added thereto to obtain a copper bromide solution.In another reaction vessel,2-amino-6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine was dissolved ina 24% hydrobromic acid solution (5 ml), and a solution of sodium nitrite(105 mg) in water (6 ml) was added dropwise under ice-cooling. Theresulting diazonium salt solution was added to the copper bromidesolution prepared above, and the reaction solution was further stirredunder ice-cooling for one hour. The reaction solution was neutralizedwith a 5 N sodium hydroxide solution. Aqueous ammonia and tert-butylmethyl ether were added and the organic layer was separated. Theresulting organic layer was washed with brine and then dried overanhydrous sodium sulfate. The drying agent was separated by filtration,and then the organic layer was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain thetitle compound (115 mg). The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 6.99 (s, 1H), 7.52 (d, J=8.0 Hz,1H), 7.66 (dd, J=8.8, 8.0 Hz, 1H), 7.76 (s, 1H).

Synthesis of (+) and(−)-2-{(E)-2-[6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

6-Bromo-2-fluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine (156 mg) and8-(2-trifluoromethylphenyl)-2-vinyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(179 mg) were dissolved in toluene (5 ml).Tris(dibenzylideneacetone)dipalladium (167 mg), tri-o-tolylphosphine(111 mg) and triethylamine (340 ul) were added and the reaction solutionwas heated and stirred in a nitrogen atmosphere at 120° C. for 1.3hours. After leaving to cool, ethyl acetate and water were added. Thereaction solution was filtered through celite and the organic layer wasseparated. The resulting organic layer was washed with brine and thendried over anhydrous sodium sulfate. The drying agent was separated byfiltration, and then the organic layer was concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography to obtain a racemate of the title compound (65 mg). Theresulting racemate was separated by CHIRALPAK™ IB manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=6:4)to obtain the title optically active compound with positive opticalrotation (20 mg, >99% ee) and the title optically active compound withnegative optical rotation (20 mg, >99% ee).

The property values of the title optically active compound with positiveoptical rotation are as follows.

ESI-MS; m/z 469 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.90-2.00 (m, 1H),2.10-2.21 (m, 1H), 2.21-2.35 (m, 1H), 2.30 (s, 3H), 2.40-2.51 (m, 1H),4.28-4.40 (m, 2H), 4.70 (dd, J=7.6, 5.6 Hz, 1H), 6.97-7.03 (m, 2H),7.22-7.28 (m, 1H), 7.37-7.52 (m, 3H), 7.57-7.77 (m, 4H).

The property values of the title optically active compound with negativeoptical rotation are as follows.

ESI-MS; m/z 469 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.90-2.00 (m, 1H),2.10-2.21 (m, 1H), 2.21-2.35 (m, 1H), 2.30 (s, 3H), 2.40-2.51 (m, 1H),4.28-4.40 (m, 2H), 4.70 (dd, J=7.6, 5.6 Hz, 1H), 6.97-7.03 (m, 2H),7.22-7.28 (m, 1H), 7.37-7.52 (m, 3H), 7.57-7.77 (m, 4H).

Examples 349 and 350 Synthesis of (+) and(−)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-yltrifluoromethanesulfonate

Pyridine (200 μL) was added to a solution of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-olsynthesized in Example 344 (200 mg) in dichloromethane (2 mL), andtrifluoromethanesulfonic anhydride (78.3 μL) was added dropwise underice-cooling. The reaction solution was stirred at room temperature forone hour. Water was added to the reaction solution under ice-cooling,followed by separatory extraction with ethyl acetate. The resultingorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (carrier: Chromatorex NH; elution solvent: heptane:ethylacetate=2:1→ethyl acetate) to obtain the title compound (64 mg).

The property value of the compound is as follows.

ESI-MS; m/z 599 [M⁺+H].

Synthesis of (+) and(−)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Triethylsilane (40.9 μL) and a 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride-dichloromethane complex (4.37 mg) were addedto a solution of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-yltrifluoromethanesulfonate (64 mg) in DMF (2 mL). The reaction solutionwas stirred at 70° C. for five hours. The reaction solution wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (carrier: Chromatorex NH; elution solvent:heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of thetitle compound (25 mg). The resulting racemate (25 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: ethanol, flow rate: 11 mL/min) to obtain the titleoptically active compound with a retention time of 21 minutes andpositive optical rotation (10 mg) and the title optically activecompound with a retention time of 30 minutes and negative opticalrotation (10 mg).

The property values of the title optically active compound with aretention time of 21 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.49 (m, 7H), 4.28-4.39 (m, 2H), 4.70 (dd,J=7.6, 6.4 Hz, 1H), 7.00-7.02 (m, 2H), 7.37-7.61 (m, 6H), 7.72 (d, J=7.6Hz, 1H), 7.76 (s, 1H), 8.67 (d, J=2.8 Hz, 1H).

The property values of the title optically active compound with aretention time of 30 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.49 (m, 7H), 4.28-4.39 (m, 2H), 4.70 (dd,J=7.6, 6.4 Hz, 1H), 7.00-7.02 (m, 2H), 7.37-7.61 (m, 6H), 7.72 (d, J=7.6Hz, 1H), 7.76 (s, 1H), 8.67 (d, J=2.8 Hz, 1H).

Examples 351 and 352 Synthesis of (+) and(−)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)-6-(2,2,2-trifluoroethoxy)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Cesium carbonate (83.7 mg) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (35.7 μL) were added to a mixture of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-olsynthesized in Example 344 (100 mg) and DMF (1.2 mL), and the reactionsolution was stirred at room temperature for four hours. Water and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (carrier: Chromatorex NH; elution solvent:heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of thetitle compound (110 mg). The resulting racemate (110 mg) was separatedby CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm, mobile phase: hexane:ethanol=5:5, flow rate: 11 mL/min) toobtain the title optically active compound with a retention time of 13minutes and positive optical rotation (51 mg) and the title opticallyactive compound with a retention time of 18 minutes and negative opticalrotation (53 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.49 (m, 7H), 4.30-4.40 (m, 2H), 4.70 (dd,J=8.4, 6.0 Hz, 2H), 4.84-4.93 (m, 2H), 6.96-7.04 (m, 3H), 7.37-7.58 (m,5H), 7.25 (d, J=7.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 18 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.49 (m, 7H), 4.30-4.40 (m, 2H), 4.70 (dd,J=8.4, 6.0 Hz, 2H), 4.84-4.93 (m, 2H), 6.96-7.04 (m, 3H), 7.37-7.58 (m,5H), 7.25 (d, J=7.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

Examples 353 and 354 Synthesis of (+) and(−)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)-6-(2,2-difluoroethoxy)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Cesium carbonate (83.7 mg) and 2-bromo-1,1-difluoroethane (34.1 mg) wereadded to a mixture of3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-olsynthesized in Example 344 (100 mg) and DMF (1.2 mL), and the reactionsolution was stirred at room temperature for 48 hours. Water and ethylacetate were added to the reaction solution, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (carrier: Chromatorex NH; elution solvent:heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of thetitle compound (80 mg). The resulting racemate (80 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: hexane:ethanol=4:6, flow rate: 11 mL/min) to obtainthe title optically active compound with a retention time of 14 minutesand positive optical rotation (33 mg) and the title optically activecompound with a retention time of 25 minutes and negative opticalrotation (35 mg).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.49 (m, 7H), 4.31-4.40 (m, 2H), 4.62-4.72(m, 3H), 5.99-6.92 (m, 1H), 6.96 (s, 1H), 6.96-7.02 (m, 3H) 7.26-7.57(m, 5H), 7.25 (d, J=7.2 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 25 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.49 (m, 7H), 4.31-4.40 (m, 2H), 4.62-4.72(m, 3H), 5.99-6.92 (m, 1H), 6.96 (s, 1H), 6.96-7.02 (m, 3H) 7.26-7.57(m, 5H), 7.25 (d, J=7.2 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).

Examples 355 and 356 Synthesis of (+) and(−)-2-{(E)-2-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]vinyl}-8-(2-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of tert-butyl(E)-3-{5-[(2,2-dimethoxyethyl)formylamino]-6-methoxypyridin-2-yl}acrylate

tert-Butyl (E)-3-(5-formylamino-6-methoxypyridin-2-yl)acrylatesynthesized according to the method in Examples 168 and 169 (4 g) wasdissolved in DMF (60 mL). Cesium carbonate (9.38 g) was added and thereaction solution was heated to 60° C. Bromoacetaldehyde dimethylacetal(2.08 mL) was added to the reaction solution. The reaction solution wasstirred for two hours, heated to 110° C. and stirred for 10 hours. Thereaction solution was left to cool. Ice water was added underice-cooling, followed by extraction with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography(carrier: Chromatorex Si; elution solvent: heptane:ethylacetate=7:1→heptane:ethyl acetate=1:2) to obtain the title compound(3.99 g). The property values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.54 (s, 9H), 3.30 (s, 6H), 3.83 (d, J=5.2 Hz,2H), 4.01 (s, 3H), 4.53 (t, J=5.2 Hz, 1H), 6.84 (d, J=15.6 Hz, 1H), 7.00(d, J=8.0 Hz, 1H), 7.46 (d, J=15.2 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 8.17(s, 1H).

Synthesis of tert-butyl(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylate

tert-Butyl(E)-3-{5-[(2,2-dimethoxyethyl)formylamino]-6-methoxypyridin-2-yl}acrylate(3.7 g) was dissolved in acetic acid (36 mL). Ammonium acetate (7 g) wasadded and the reaction solution was stirred at 135° C. for two hours.The reaction solution was concentrated under reduced pressure. Asaturated sodium bicarbonate solution and ethyl acetate were added andthe organic layer was separated. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (carrier: Chromatorex NH;elution solvent: heptane:ethyl acetate=9:1→heptane:ethyl acetate=1:2) toobtain the title compound (490 mg).

The property value of the compound is as follows.

ESI-MS; m/z 302 [M⁺+H].

Synthesis of (E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylicacid

A solution of trifluoroacetic acid (3 mL) in dichloromethane (1.5 mL)was added to tert-butyl(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylate (490 mg)under ice-cooling, and the reaction solution was stirred at roomtemperature for one hour. The reaction solution was concentrated underreduced pressure, diluted with chloroform and then concentrated underreduced pressure. Diethyl ether was added to the residue, and theprecipitated solid was collected by filtration. The solid was washedwith diethyl ether to obtain the title compound as a solid (345 mg). Theproperty values of the compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 4.00 (s, 3H), 6.88 (d, J=15.6 Hz, 1H), 7.52-7.70(m, 4H), 7.90 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 9.18 (s, 1H).

Synthesis of(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]acrylamide

IPEA (742 μL), EDC (206 mg) and HOBT (146 mg) were added to a mixture of1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (185 mg),(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylic acid (340 mg)and DMF (5 mL), and the reaction solution was stirred at roomtemperature for 14 hours. A saturated sodium bicarbonate solution wasadded to the reaction solution, followed by extraction with ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (carrier: Chromatorex NH; elution solvent: ethylacetate→ethyl acetate:methanol=9:1) to obtain the title compound (453mg). The property value of the compound is as follows.

ESI-MS; m/z 486 [M⁺+H].

Synthesis of (+) and(−)-2-{(E)-2-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]vinyl}-8-(2-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Phosphorus oxychloride (9 mL) was added to(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]acrylamide(340 mg), and the reaction solution was stirred at 100° C. for 35minutes. The reaction solution was concentrated under reduced pressure.The resulting residue was diluted with acetic acid (5 mL). Then,ammonium acetate (1.43 g) was added and the reaction solution wasstirred at 140° C. for one hour and 15 minutes. The reaction solutionwas concentrated under reduced pressure. Ethyl acetate and a saturatedsodium bicarbonate solution were added to the residue, and the organiclayer was separated. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel chromatography (carrier: Chromatorex NH; elution solvent:heptane:ethyl acetate=2:1→ethyl acetate) to obtain a racemate of thetitle compound (200 mg). The racemate (200 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm, mobile phase: hexane:ethanol=5:5, flow rate: 11 mL/min) to obtainthe title optically active compound with a retention time of 16 minutesand positive optical rotation (70 mg) and the title optically activecompound with a retention time of 34 minutes and negative opticalrotation (75 mg).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.50 (m, 4H), 4.03 (s, 3H), 4.29-4.40 (m,2H), 4.69 (dd, J=6.4, 6.0 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 7.01 (d,J=7.6 Hz, 1H), 7.17 (brm, 1H), 7.23-7.24 (m, 1H), 7.37-7.50 (m, 4H),7.65 (d, J=15.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.85 (m, 1H).

The property values of the title optically active compound with aretention time of 34 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.50 (m, 4H), 4.03 (s, 3H), 4.29-4.40 (m,2H), 4.69 (dd, J=6.4, 6.0 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 7.01 (d,J=7.6 Hz, 1H), 7.17 (brm, 1H), 7.23-7.24 (m, 1H), 7.37-7.50 (m, 4H),7.65 (d, J=15.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.85 (m, 1H).

Examples 357 and 358 Synthesis of (+) and(−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]propenyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-butenoicacid ditrifluoroacetate

Sodium hydride (401 mg; containing 60 wt % of mineral oil) was added toa solution of tert-butyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate(1.58 g) and trimethylsulfonium iodide (2.21 g) in DMSO (15 mL) at 0° C.Then, the reaction solution was stirred at room temperature for onehour. Ice water and ethyl acetate were added to the reaction solution,and the organic layer was separated. The resulting organic layer waswashed with brine and then dried over anhydrous magnesium sulfate. Theorganic layer was concentrated under reduced pressure. The residue waspurified by NH-silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain a crude product. Trifluoroaceticacid (6 mL) was added to a solution of the crude product in methylenechloride (3 mL) at room temperature, and the reaction solution wasstirred at room temperature for two hours. The reaction solvent wasremoved under reduced pressure, followed by azeotropic distillation withchloroform. Then, the resulting solid was filtered, washed with diethylether and dried to obtain 1.05 g of the title compound. The propertyvalue of the compound is as follows.

ESI-MS; m/z 274 [M⁺+H].

Synthesis of (+) and(−)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]propenyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (125 mg) was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-butenoicacid ditrifluoroacetate (300 mg) and1-amino-3-(4-fluorophenyl)piperidin-2-one (163 mg) according to themethod in Examples 168 and 169. The resulting racemate was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane-ethanol system) to obtain the title opticallyactive compound with a retention time of 18.7 minutes and positiveoptical rotation (41.7 mg, >99% ee) and the title optically activecompound with a retention time of 27.9 minutes and negative opticalrotation (41.8 mg, >99% ee).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 464 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.00-2.18 (m, 2H),2.18-2.28 (m, 1H), 2.30 (s, 3H), 2.30-2.40 (m, 1H), 2.63 (s, 3H), 4.05(s, 3H), 4.30-4.36 (m, 3H), 6.97 (s, 1H), 7.00-7.05 (m, 2H), 7.10-7.14(m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.2Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 464 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.00-2.18 (m, 2H),2.18-2.28 (m, 1H), 2.30 (s, 3H), 2.30-2.40 (m, 1H), 2.63 (s, 3H), 4.05(s, 3H), 4.30-4.36 (m, 3H), 6.97 (s, 1H), 7.00-7.05 (m, 2H), 7.10-7.14(m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.2Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

Examples 359, 360, 361 and 362 Synthesis of (5R,8R), (5S,8S), (5R,8S)and(5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Synthesis of 2-(2-trifluoromethylphenyl)pentanedioic acid 5-tert-butylester 1-methyl ester

Methyl 2-trifluoromethylphenylacetate (5 g) was dissolved in THF (75mL). Potassium tert-butoxide (2.71 g) was added under ice-cooling, andthe reaction solution was stirred for 30 minutes. tert-Butyl3-bromopropionate (3.83 mL) was added to the reaction solution. Thereaction solution was gradually heated until room temperature andstirred for four hours. A 1 N hydrochloric acid aqueous solution wasadded to the reaction solution, followed by extraction with ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (carrier: Chromatorex Si; elution solvent:heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1) to obtain thetitle compound (6 g). The property values of the compound are asfollows.

¹H-NMR (CDCl₃) δ (ppm): 1.42 (s, 9H), 2.02-2.43 (m, 4H), 3.66 (s, 3H),4.06 (dd, J=7.2, 7.2 Hz, 1H), 7.35-7.41 (m, 1H), 7.50-7.67 (m, 3H).

Synthesis of methyl 5-oxo-2-(2-trifluoromethylphenyl)hexanoate

2-(2-Trifluoromethylphenyl)pentanedioic acid 5-tert-butyl ester 1-methylester (3 g) was dissolved in dichloromethane (30 mL). Trifluoroaceticacid (12 mL) was added and the reaction solution was stirred at roomtemperature for one hour. The reaction solution was concentrated underreduced pressure, and the resulting residue was dissolved in toluene (60mL). Thionyl chloride (1.89 mL) was added and the reaction solution wasstirred at 80° C. for three hours. The reaction solution wasconcentrated under reduced pressure and diluted with THF (50 mL). Then,tributylphosphine (2.37 mL) was added at −20° C. and the reactionsolution was stirred for 20 minutes. A 0.97 M solution ofmethylmagnesium bromide in THF (9.78 mL) was added dropwise to thereaction solution, and the reaction solution was stirred for 15 minutes.Then, a 1 N hydrochloric acid aqueous solution was added, followed byextraction with ethyl acetate. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (carrier: Chromatorex Si;elution solvent: heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1)to obtain the title compound (728 mg). The property values of thecompound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.01-2.51 (m, 7H), 3.65 (s, 3H), 3.98-4.02 (m,1H), 7.35-7.38 (m, 1H), 7.51-7.57 (m, 2H), 7.56 (d, J=8.0 Hz, 1H).

Synthesis of 1-amino-6-methyl-3-(2-trifluoromethylphenyl)piperidin-2-one

Methyl 5-oxo-2-(2-trifluoromethylphenyl)hexanoate (728 mg) was dissolvedin methanol (15.2 mL). Sodium borohydride (47.8 mg) was added underice-cooling, and the reaction solution was stirred at the sametemperature for 30 minutes. A 1 N hydrochloric acid aqueous solution wasadded to the reaction solution, followed by extraction with ethylacetate. The resulting organic layer was dried over magnesium sulfateand then concentrated under reduced pressure. The resulting residue wasdissolved in chloroform (15 mL). Thionyl chloride (576 μL) was added andthe reaction solution was stirred at 50° C. for three hours. Thereaction solution was concentrated under reduced pressure. The resultingresidue was purified by silica gel chromatography (carrier: ChromatorexSi; elution solvent: heptane:ethyl acetate=19:1→heptane:ethylacetate=1:1) to obtain methyl5-chloro-2-(2-trifluoromethylphenyl)hexanoate (380 mg) as a diastereomermixture. The mixture (320 mg) was dissolved in ethanol (7.8 mL).Hydrazine monohydrate (1.5 mL) was added and the reaction solution wasstirred at 100° C. for 14 hours. The reaction solution was concentratedunder reduced pressure. A saturated sodium bicarbonate solution wasadded to the residue, followed by extraction with ethyl acetate. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (carrier: Chromatorex Si; elution solvent: heptane:ethylacetate=19:1→heptane:ethyl acetate=1:1) to obtain the title compound(380 mg).

The property values of the compound are as follows.

ESI-MS; m/z 273 [M⁺+H].

Synthesis of (5R,8R), (5S,8S), (5R,8S) and(5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound (140 mg) was obtained using1-amino-6-methyl-3-(2-trifluoromethylphenyl)piperidin-2-one (210 mg) asa starting material according to the method in Examples 168 and 169. Theresulting racemate (140 mg) was separated by CHIRALPAK™ IB manufacturedby Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase;hexane:ethanol=8:2, flow rate: 10 mL/min) to obtain the title opticallyactive compound with a retention time of 30 minutes and positive opticalrotation (18 mg), the title optically active compound with a retentiontime of 33 minutes and positive optical rotation (10 mg), the titleoptically active compound with a retention time of 43 minutes andnegative optical rotation (15 mg) and the title optically activecompound with a retention time of 71 minutes and negative opticalrotation (14 mg).

The property values of the title optically active compound with aretention time of 30 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.70-2.34 (m, 10H), 4.03 (s, 3H), 4.49-4.55 (m,1H), 4.73 (dd, J=6.8, 6.8 Hz, 1H), 6.91-6.94 (m, 3H), 7.37-7.50 (m, 4H),7.66 (d, J=15.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 33 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.63-1.93 (m, 5H), 2.29-2.48 (m, 5H), 4.03 (s,3H), 4.42-4.50 (m, 1H), 4.63-4.67 (m, 1H), 6.91-6.95 (m, 2H), 7.03-7.06(d, J=7.6 Hz, 1H), 7.36-7.50 (m, 4H), 7.64 (d, J=15.6 Hz, 1H), 7.72 (d,J=7.6 Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 43 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.63-1.93 (m, 5H), 2.29-2.48 (m, 5H), 4.03 (s,3H), 4.42-4.50 (m, 1H), 4.63-4.67 (m, 1H), 6.91-6.95 (m, 2H), 7.03-7.06(d, J=7.6 Hz, 1H), 7.36-7.50 (m, 4H), 7.64 (d, J=15.6 Hz, 1H), 7.72 (d,J=7.6 Hz, 1H), 7.76 (s, 1H).

The property values of the title optically active compound with aretention time of 71 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.70-2.34 (m, 10H), 4.03 (s, 3H), 4.49-4.55 (m,1H), 4.73 (dd, J=6.8, 6.8 Hz, 1H), 6.91-6.94 (m, 3H), 7.37-7.50 (m, 4H),7.66 (d, J=15.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.76 (s, 1H).

Example 363 Synthesis of2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol

2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-Trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine(50 mg) was dissolved in DMF (3 mL). Sodium hydride (containing 40% ofmineral oil, 8.3 mg) was added and the reaction solution was stirred atroom temperature for 10 minutes. The reaction solution was internallyreplaced with oxygen. The reaction solution was bubbled with oxygen andstirred for two hours. A sodium thiosulfate solution was added to thereaction solution, and the reaction solution was stirred at roomtemperature for 30 minutes. Ethyl acetate was added to the reactionsolution and the organic layer was separated. The organic layer wasdried over magnesium sulfate and concentrated under reduced pressure.The resulting residue was purified by silica gel chromatography(carrier: Chromatorex Si; elution solvent: heptane:ethylacetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) to obtain thetitle compound (10 mg). The property values of the compound are asfollows.

ESI-MS; m/z 497 [M⁺+H].

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.62 (m, 7H), 3.97 (s, 3H), 4.16-4.41 (m,2H), 6.74 (d, J=7.6 Hz, 1H), 6.91 (s, 1H), 7.29-7.60 (m, 5H), 7.72-7.75(m, 2H), 7.86 (s, 1H).

Examples 364 and 365 Synthesis of (+) and(−)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

A racemate of the title compound was obtained from8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(133 mg) according to the method in Examples 53 and 54. The resultingracemate was separated by CHIRALPAK™ IC manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the titleoptically active compound with a retention time of 6.1 minutes andpositive optical rotation (28.7 mg, >99% ee) and the title opticallyactive compound with a retention time of 7.0 minutes and negativeoptical rotation (25.5 mg, >99% ee).

The property values of the title compound with positive optical rotationare as follows.

ESI-MS; m/z 465 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.12 (m, 1H),2.14-2.21 (m, 1H), 2.29 (s, 3H), 2.30-2.50 (m, 2H), 4.00 (s, 3H),4.23-4.37 (m, 2H), 6.75 (m, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.90-6.94 (m,3H), 7.38 (d, J=15.6 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.62 (d, J=15.6Hz, 1H), 7.80 (s, 1H).

The property values of the title compound with negative optical rotationare as follows.

ESI-MS; m/z 465 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.01-2.12 (m, 1H),2.14-2.21 (m, 1H), 2.29 (s, 3H), 2.30-2.50 (m, 2H), 4.00 (s, 3H),4.23-4.37 (m, 2H), 6.75 (m, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.90-6.94 (m,3H), 7.38 (d, J=15.6 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.62 (d, J=15.6Hz, 1H), 7.80 (s, 1H).

Example 366 Synthesis of2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyridine

2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol(56 mg) was dissolved in dichloromethane (2 ml). Diethylaminosulfurtrifluoride (45 ul) was added under ice-cooling, and the reactionsolution was stirred at room temperature for three hours. Thereafter,diethylaminosulfur trifluoride (45 ul) was added again at roomtemperature, and the reaction solution was further stirred at roomtemperature overnight. Ethyl acetate and water were added to thereaction solution, and the organic layer was separated. The resultingorganic layer was washed with brine and then dried over anhydrous sodiumsulfate. The drying agent was separated by filtration and then theorganic layer was concentrated under reduced pressure. The residue wasseparated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries,Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the titlecompound (20 mg). The property values of the compound are as follows.

ESI-MS; m/z 479 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 2.93 (td,J=8.2, 4.4 Hz, 2H), 4.03 (s, 3H), 4.44 (t, J=8.2 Hz, 2H), 6.27 (t, J=4.4Hz, 1H), 6.91-6.96 (m, 2H), 7.39-7.55 (m, 4H), 7.60-7.66 (m, 2H),7.74-7.78 (m, 2H).

Examples 367 and 368 Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A racemate of the title compound (190 mg) was obtained using2-(trifluoromethyl)benzaldehyde (3 g) as a starting material accordingto the method in Examples 257 and 258. The resulting racemate (190 mg)was separated by CHIRALPAK™ IB manufactured by Daicel ChemicalIndustries, Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=1:1, flowrate: 11 mL/min) to obtain the title optically active compound with aretention time of 27 minutes and positive optical rotation (38 mg) andthe title optically active compound with a retention time of 41 minutesand negative optical rotation (37 mg).

The property values of the title optically active compound with aretention time of 27 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 4.04 (s, 3H), 4.17-4.53 (m, 4H),6.26 (s, 1H), 6.93-6.95 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.43-7.58 (m,4H), 7.64 (d, J=15.6 Hz, 1H), 7.77-7.80 (m, 2H).

The property values of the title optically active compound with aretention time of 41 minutes are as follows.

¹H-NMR (CDCl₃) δ (ppm): 2.29 (s, 3H), 4.04 (s, 3H), 4.17-4.53 (m, 4H),6.26 (s, 1H), 6.93-6.95 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.43-7.58 (m,4H), 7.64 (d, J=15.6 Hz, 1H), 7.77-7.80 (m, 2H).

Example 369 Synthesis of4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

146 mg of the racemic title compound was obtained from(E)-N-[3-(4-fluorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide(240 mg) by the same method as in Example 232. The property values ofthe compound are as follows.

ESI-MS; m/z 432 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.33-2.42 (m, 2H), 3.83 (t, J=5.6 Hz, 2H), 4.05 (s, 3H), 4.24 (t, J=6.0Hz, 2H), 6.93-6.98 (m, 2H), 7.07-7.14 (m, 2H), 7.38 (d, J=15.6 Hz, 1H),7.45-7.56 (m, 4H), 7.77 (d, J=1.2 Hz, 1H).

Example 370 Synthesis of2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

320 mg of the title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)-tetrahydropyrimidin-1-yl]acrylamide(474 mg) by the same method as in Example 232. The property values ofthe compound are as follows.

ESI-MS; m/z 482 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.25-2.55 (m, 2H), 2.29(d, J=0.8 Hz, 3H), 3.57-3.73 (m, 2H), 4.01 (s, 3H), 4.20-4.34 (m, 2H),6.88 (d, J=8.0 Hz, 1H), 6.93-6.96 (m, 1H), 7.26-7.32 (m, 1H), 7.43 (d,J=8.0 Hz, 1H), 7.46-7.54 (m, 3H), 7.64-7.70 (m, 1H), 7.74 (d, J=1.2 Hz,1H), 7.77-7.82 (m, 1H).

Examples 371 and 372 Synthesis of (R) and(S)-4-(2,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

374 mg of the racemic title compound was obtained from(E)-N-[3-(2,4-difluorophenyl)-4-methyl-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide(500 mg) by the same method as in Example 232. The racemic titlecompound (250 mg) was separated by CHIRALPAK™ IC manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethylacetate:methanol=2:3) to obtain the title optically active compound witha retention time of 16 minutes (110 mg) and the title optically activecompound with a retention time of 19 minutes (110 mg).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 464 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.23 (d, J=6.4 Hz, 3H),2.11-2.20 (m, 1H), 2.29 (s, 3H), 2.38-2.48 (m, 1H), 3.93-4.02 (m, 1H),4.03 (s, 3H), 4.26 (t, J=6.4 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.92-7.00(m, 3H), 7.29 (d, J=15.6 Hz, 1H), 7.39-7.47 (m, 2H), 7.49 (d, J=15.6 Hz,1H), 7.76 (brs, 1H).

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

ESI-MS; m/z 464 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.23 (d, J=6.4 Hz, 3H),2.11-2.20 (m, 1H), 2.29 (s, 3H), 2.38-2.48 (m, 1H), 3.93-4.02 (m, 1H),4.03 (s, 3H), 4.26 (t, J=6.4 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.92-7.00(m, 3H), 7.29 (d, J=15.6 Hz, 1H), 7.39-7.47 (m, 2H), 7.49 (d, J=15.6 Hz,1H), 7.76 (brs, 1H).

Examples 373 and 374 Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine

374 mg of the racemic title compound was obtained from(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[4-methyl-2-oxo-3-(2-trifluoromethylphenyl)-tetrahydropyrimidin-1-yl]acrylamide(494 mg) by the same method as in Example 232. The racemic titlecompound (220 mg) was separated by CHIRALPAK™ IC manufactured by DaicelChemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethylacetate:methanol=1:1) and solidified with ethyl acetate and heptane toobtain the title optically active compound with positive opticalrotation and a retention time of 2 minutes (97 mg) and the titleoptically active compound with negative optical rotation and a retentiontime of 5 minutes (92 mg).

The property values of the title optically active compound with aretention time of 2 minutes are as follows.

ESI-MS; m/z 496 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.25-1.34 (m, 3H),2.04-2.15 (m, 1H), 2.28 (s, 3H), 2.46-2.60 (m, 1H), 3.91-4.03 (m, 1H),4.01 (s, 3H), 4.20-4.36 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 6.94 (brs, 1H),7.23-7.30 (m, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.44-7.56 (m, 3H), 7.65-7.71(m, 1H), 7.73-7.76 (m, 1H), 7.79-7.84 (m, 1H).

The property values of the title optically active compound with aretention time of 5 minutes are as follows.

ESI-MS; m/z 496 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.25-1.34 (m, 3H),2.04-2.15 (m, 1H), 2.28 (s, 3H), 2.46-2.60 (m, 1H), 3.91-4.03 (m, 1H),4.01 (s, 3H), 4.20-4.36 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 6.94 (brs, 1H),7.23-7.30 (m, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.44-7.56 (m, 3H), 7.65-7.71(m, 1H), 7.73-7.76 (m, 1H), 7.79-7.84 (m, 1H).

Examples 375 and 376 Synthesis of (R) and(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

60 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride (250 mg) and 4-chloro-2-phenylbutyric acid hydrazidehydrochloride (191 mg) by the same method as in Examples 253 and 254.The racemic title compound (60 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain the title optically active compoundwith a retention time of 13 minutes (13 mg) and the title opticallyactive compound with a retention time of 23 minutes (15 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

ESI-MS; m/z 399 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.66-2.78 (m, 1H), 3.20-3.32 (m, 1H), 4.07 (s, 3H), 4.17-4.27 (m, 1H),4.30-4.40 (m, 1H), 4.46 (dd, J=6.4, 8.4 Hz, 1H), 6.93-6.98 (m, 2H),7.23-7.44 (m, 5H), 7.48 (d, J=8.0 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67(d, J=15.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 23 minutes are as follows.

ESI-MS; m/z 399 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.66-2.78 (m, 1H), 3.20-3.32 (m, 1H), 4.07 (s, 3H), 4.17-4.27 (m, 1H),4.30-4.40 (m, 1H), 4.46 (dd, J=6.4, 8.4 Hz, 1H), 6.93-6.98 (m, 2H),7.23-7.44 (m, 5H), 7.48 (d, J=8.0 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67(d, J=15.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

Examples 377 and 378 Synthesis of (+) and(−)-7-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

264 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate(800 mg) and 4-chloro-2-(4-fluorophenyl)butyric acid hydrazidehydrochloride (807 mg) by the same method as in Examples 253 and 254.The racemic title compound (264 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain the title optically active compoundwith positive optical rotation and a retention time of 11 minutes (87mg) and the title optically active compound with negative opticalrotation and a retention time of 22 minutes (88 mg).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

ESI-MS; m/z 417 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.62-2.73 (m, 1H), 3.20-3.31 (m, 1H), 4.07 (s, 3H), 4.18-4.26 (m, 1H),4.31-4.38 (m, 1H), 4.46 (dd, J=6.8, 8.4 Hz, 1H), 6.94-6.98 (m, 2H),7.03-7.10 (m, 2H), 7.22-7.28 (m, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.52 (d,J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H).

The property values of the title optically active compound with aretention time of 22 minutes are as follows.

ESI-MS; m/z 417 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.62-2.73 (m, 1H), 3.20-3.31 (m, 1H), 4.07 (s, 3H), 4.18-4.26 (m, 1H),4.31-4.38 (m, 1H), 4.46 (dd, J=6.8, 8.4 Hz, 1H), 6.94-6.98 (m, 2H),7.03-7.10 (m, 2H), 7.22-7.28 (m, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.52 (d,J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H).

Examples 379 and 380 Synthesis of (R) and(S)-7-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

71 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride (500 mg) and 4-chloro-2-(3,4-difluorophenyl)butyric acidhydrazide hydrochloride (500 mg) by the same method as in Examples 253and 254. The racemic title compound (71 mg) was separated by CHIRALPAK™IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain the title optically active compoundwith a retention time of 11 minutes (20 mg) and the title opticallyactive compound with a retention time of 24 minutes (19 mg).

The property values of the title optically active compound with aretention time of 11 minutes are as follows.

ESI-MS; m/z 435 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.62-2.74(m, 1H), 3.21-3.32 (m, 1H), 4.07 (s, 3H), 4.18-4.27 (m, 1H), 4.31-4.40(m, 1H), 4.41-4.48 (m, 1H), 6.94-7.00 (m, 2H), 7.01-7.07 (m, 1H),7.10-7.21 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.66(d, J=15.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 24 minutes are as follows.

ESI-MS; m/z 435 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.62-2.74(m, 1H), 3.21-3.32 (m, 1H), 4.07 (s, 3H), 4.18-4.27 (m, 1H), 4.31-4.40(m, 1H), 4.41-4.48 (m, 1H), 6.94-7.00 (m, 2H), 7.01-7.07 (m, 1H),7.10-7.21 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.66(d, J=15.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

Examples 381 and 382 Synthesis of (+) and(−)-7-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

266 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate(1.0 g) and 4-chloro-2-(2,3-difluorophenyl)butyric acid hydrazidehydrochloride (1.05 g) by the same method as in Examples 253 and 254.The racemic title compound (266 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain the title optically active compoundwith positive optical rotation and a retention time of 13 minutes (60mg) and the title optically active compound with negative opticalrotation and a retention time of 27 minutes (83 mg).

The property values of the title optically active compound with aretention time of 13 minutes are as follows.

ESI-MS; m/z 435 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.63-2.74(m, 1H), 3.28-3.40 (m, 1H), 4.07 (s, 3H), 4.22-4.31 (m, 1H), 4.33-4.41(m, 1H), 4.71 (dd, J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 3H), 7.04-7.18 (m,2H), 7.49 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 27 minutes are as follows.

ESI-MS; m/z 435 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.63-2.74(m, 1H), 3.28-3.40 (m, 1H), 4.07 (s, 3H), 4.22-4.31 (m, 1H), 4.33-4.41(m, 1H), 4.71 (dd, J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 3H), 7.04-7.18 (m,2H), 7.49 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6Hz, 1H), 7.78 (d, J=1.2 Hz, 1H).

Examples 383 and 384 Synthesis of (+) and(−)-7-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

371 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride (2.2 g) and 4-chloro-2-(3,5-difluorophenyl)butyric acidhydrazide hydrochloride (1.7 g) by the same method as in Examples 253and 254. The racemic title compound (371 mg) was separated by CHIRALPAK™IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain the title optically active compoundwith positive optical rotation and a retention time of 14 minutes (125mg) and the title optically active compound with negative opticalrotation and a retention time of 35 minutes (134 mg).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

ESI-MS; m/z 435 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.65-2.75 (m, 1H), 3.23-3.33 (m, 1H), 4.08 (s, 3H), 4.18-4.27 (m, 1H),4.32-4.40 (m, 1H), 4.42-4.49 (m, 1H), 6.73-6.80 (m, 1H), 6.81-6.89 (m,2H), 6.95-7.01 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H),7.66 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 35 minutes are as follows.

ESI-MS; m/z 435 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.65-2.75 (m, 1H), 3.23-3.33 (m, 1H), 4.08 (s, 3H), 4.18-4.27 (m, 1H),4.32-4.40 (m, 1H), 4.42-4.49 (m, 1H), 6.73-6.80 (m, 1H), 6.81-6.89 (m,2H), 6.95-7.01 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H),7.66 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

Examples 385 and 386 Synthesis of (R) and(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(2,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

120 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride (500 mg) and 4-chloro-2-(2,4,5-trifluorophenyl)butyricacid hydrazide hydrochloride (500 mg) by the same method as in Examples253 and 254. The racemic title compound (120 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=1:1) to obtain the title opticallyactive compound with a retention time of 9 minutes (30 mg) and the titleoptically active compound with a retention time of 22 minutes (28 mg).

The property values of the title optically active compound with aretention time of 9 minutes are as follows.

ESI-MS; m/z 453 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.58-2.70 (m, 1H), 3.27-3.38 (m, 1H), 4.08 (s, 3H), 4.20-4.30 (m, 1H),4.31-4.39 (m, 1H), 4.59-4.66 (m, 1H), 6.94-7.04 (m, 3H), 7.09-7.17 (m,1H), 7.49 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 22 minutes are as follows.

ESI-MS; m/z 453 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=0.8 Hz, 3H),2.58-2.70 (m, 1H), 3.27-3.38 (m, 1H), 4.08 (s, 3H), 4.20-4.30 (m, 1H),4.31-4.39 (m, 1H), 4.59-4.66 (m, 1H), 6.94-7.04 (m, 3H), 7.09-7.17 (m,1H), 7.49 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).

Examples 387 and 388 Synthesis of (+) and(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

226 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate(730 mg) and 4-chloro-2-(2,3,4-trifluorophenyl)butyric acid hydrazidehydrochloride (794 mg) by the same method as in Examples 253 and 254.The racemic title compound (226 mg) was separated by CHIRALPAK™ IBmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=1:1) to obtain the title optically active compoundwith positive optical rotation and a retention time of 14 minutes (52mg) and the title optically active compound with negative opticalrotation and a retention time of 25 minutes (78 mg).

The property values of the title optically active compound with aretention time of 14 minutes are as follows.

ESI-MS; m/z 453 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.60-2.71(m, 1H), 3.28-3.39 (m, 1H), 4.07 (s, 3H), 4.22-4.30 (m, 1H), 4.32-4.40(m, 1H), 4.66 (dd, J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 4H), 7.49 (d, J=7.6Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.79 (d,J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 25 minutes are as follows.

ESI-MS; m/z 453 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.60-2.71(m, 1H), 3.28-3.39 (m, 1H), 4.07 (s, 3H), 4.22-4.30 (m, 1H), 4.32-4.40(m, 1H), 4.66 (dd, J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 4H), 7.49 (d, J=7.6Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.79 (d,J=1.2 Hz, 1H).

Examples 389 and 390 Synthesis of (R) and(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

55 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidatedihydrochloride (250 mg) and 4-chloro-2-(2-trifluoromethylphenyl)butyricacid hydrazide hydrochloride (212 mg) synthesized from(2-trifluoromethylphenyl)acetic acid by the same method as in Examples253 and 254. The racemic title compound (55 mg) was separated byCHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25cm; mobile phase: hexane:ethanol=4:1) to obtain the title opticallyactive compound with a retention time of 16 minutes (12 mg) and thetitle optically active compound with a retention time of 28 minutes (11mg).

The property values of the title optically active compound with aretention time of 16 minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.54-2.65(m, 1H), 3.27-3.38 (m, 1H), 4.07 (s, 3H), 4.20-4.30 (m, 1H), 4.31-4.40(m, 1H), 4.87 (dd, J=8.0, 8.0 Hz, 1H), 6.93-6.99 (m, 2H), 7.09 (d, J=7.6Hz, 1H), 7.39-7.45 (m, 1H), 7.46-7.57 (m, 3H), 7.65-7.75 (m, 2H), 7.79(s, 1H).

The property values of the title optically active compound with aretention time of 28 minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.54-2.65(m, 1H), 3.27-3.38 (m, 1H), 4.07 (s, 3H), 4.20-4.30 (m, 1H), 4.31-4.40(m, 1H), 4.87 (dd, J=8.0, 8.0 Hz, 1H), 6.93-6.99 (m, 2H), 7.09 (d, J=7.6Hz, 1H), 7.39-7.45 (m, 1H), 7.46-7.57 (m, 3H), 7.65-7.75 (m, 2H), 7.79(s, 1H).

Examples 391 and 392 Synthesis of (R) and(S)-7-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

151 mg of the racemic title compound was obtained from ethyl(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate(550 mg) and 4-chloro-2-(5-fluoro-2-trifluoromethylphenyl)butyric acidhydrazide hydrochloride (680 mg) by the same method as in Examples 253and 254. The racemic title compound (151 mg) was separated by CHIRALPAK™IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: hexane:ethanol=4:1) to obtain the title optically active compoundwith a retention time of 18 minutes (46 mg) and the title opticallyactive compound with a retention time of 34 minutes (34 mg).

The property value of the title optically active compound with aretention time of 18 minutes is as follows.

ESI-MS; m/z 485 [M⁺+H].

The property values of the title optically active compound with aretention time of 34 minutes are as follows.

ESI-MS; m/z 485 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.54-2.65(m, 1H), 3.28-3.40 (m, 1H), 4.08 (s, 3H), 4.20-4.30 (m, 1H), 4.32-4.41(m, 1H), 4.87 (t, J=7.6 Hz, 1H), 6.78-6.84 (m, 1H), 6.94-7.01 (m, 2H),7.07-7.14 (m, 1H), 7.47-7.56 (m, 2H), 7.68 (d, J=15.6 Hz, 1H), 7.74 (dd,J=5.6, 8.8 Hz, 1H), 7.79 (brs, 1H).

Example 393 Synthesis of2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

50 mg of the title compound was obtained by the same method as inExamples 53 and 54 from the optically active compound synthesized by themethod in Examples 375 and 376 with a retention time of 13 minutes,2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole(112 mg). The property value of the compound is as follows.

ESI-MS; m/z 415 [M⁺+H].

Examples 394 and 395 Synthesis of (+) and(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

230 mg of the racemic title compound was obtained from1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (343 mg) and(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid(500 mg) by the same method as in Examples 194 and 195. The racemictitle compound (220 mg) was separated by CHIRALPAK™ IC manufactured byDaicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: methanol) toobtain the title optically active compound with positive opticalrotation and a retention time of 16 minutes (92 mg) and the titleoptically active compound with negative optical rotation and a retentiontime of 19 minutes (79 mg).

The property value of the title optically active compound with aretention time of 16 minutes is as follows.

ESI-MS; m/z 481 [M⁺+H].

The property values of the title optically active compound with aretention time of 19 minutes are as follows.

ESI-MS; m/z 481 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.90-2.01 (m, 1H),2.10-2.35 (m, 2H), 2.29 (s, 3H), 2.43-2.52 (m, 1H), 3.95 (s, 3H),4.27-4.41 (m, 2H), 4.69 (dd, J=6.0, 8.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H),7.08 (d, J=16.4 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.44-7.53 (m,4H), 7.73 (d, J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.34 (s, 1H).

Examples 396 and 397 Synthesis of (+) and(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

167 mg of the racemic title compound was obtained from ethyl(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidatedihydrochloride (1.0 g) and 4-chloro-2-phenylbutyric acid hydrazidehydrochloride (965 mg) by the same method as in Examples 255 and 256.The racemic title compound (167 mg) was separated by CHIRALPAK™ AD-Hmanufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobilephase: ethanol) to obtain the title optically active compound withpositive optical rotation and a retention time of 28 minutes (50 mg) andthe title optically active compound with negative optical rotation and aretention time of 42 minutes (47 mg).

The property values of the title optically active compound with aretention time of 28 minutes are as follows.

ESI-MS; m/z 399 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.67-2.78(m, 1H), 3.21-3.32 (m, 1H), 3.99 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.40(m, 1H), 4.46 (dd, J=6.8, 8.8 Hz, 1H), 7.12 (d, J=16.0 Hz, 1H),7.22-7.34 (m, 3H), 7.34-7.41 (m, 2H), 7.47-7.56 (m, 2H), 7.58 (d, J=16.0Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 8.36 (s, 1H).

The property values of the title optically active compound with aretention time of 42 minutes are as follows.

ESI-MS; m/z 399 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (s, 3H), 2.67-2.78(m, 1H), 3.21-3.32 (m, 1H), 3.99 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.40(m, 1H), 4.46 (dd, J=6.8, 8.8 Hz, 1H), 7.12 (d, J=16.0 Hz, 1H),7.22-7.34 (m, 3H), 7.34-7.41 (m, 2H), 7.47-7.56 (m, 2H), 7.58 (d, J=16.0Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 8.36 (s, 1H).

Examples 398 and 399 Synthesis of (+) and(−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

230 mg of the racemic title compound was obtained from ethyl(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidatedihydrochloride (1.0 g) and 4-chloro-2-(2-trifluoromethylphenyl)butyricacid hydrazide hydrochloride (1.17 g) by the same method as in Examples255 and 256. The racemic title compound (230 mg) was separated byCHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2cm×25 cm; mobile phase: hexane:ethanol=4:1) to obtain the titleoptically active compound with positive optical rotation and a retentiontime of 29 minutes (41 mg) and the title optically active compound withnegative optical rotation and a retention time of 33 minutes (43 mg).

The property values of the title optically active compound with aretention time of 29 minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.54-2.65 (m, 1H), 3.28-3.38 (m, 1H), 3.99 (s, 3H), 4.20-4.29 (m, 1H),4.32-4.40 (m, 1H), 4.87 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.13(d, J=16.4 Hz, 1H), 7.42 (dd, J=7.6, 7.6 Hz, 1H), 7.47-7.55 (m, 3H),7.57 (d, J=16.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H),8.36 (d, J=1.2 Hz, 1H).

The property values of the title optically active compound with aretention time of 33 minutes are as follows.

ESI-MS; m/z 467 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 2.30 (d, J=1.2 Hz, 3H),2.54-2.65 (m, 1H), 3.28-3.38 (m, 1H), 3.99 (s, 3H), 4.20-4.29 (m, 1H),4.32-4.40 (m, 1H), 4.87 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.13(d, J=16.4 Hz, 1H), 7.42 (dd, J=7.6, 7.6 Hz, 1H), 7.47-7.55 (m, 3H),7.57 (d, J=16.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H),8.36 (d, J=1.2 Hz, 1H).

Reference Example 5 Another Example of Method for Preparation of theCompound of the Example 195 Synthesis of5-Chloro-2-(2-trifluoromethylphenyl)pentanenitrile

(2-Trifluoromethylphenyl)acetonitrile (12.47 g, 67.3 mmol) was dissolvedin THF (87.3 mL) at room temperature under nitrogen atmosphere. Thereaction solution was cooled to −10° C. Then, potassium tert-butoxide(7.93 g, 70.7 mmol) was added to the reaction solution and the reactionmixture was stirred at −10° C. for 10 minutes. 1-Bromo-3-chloropropane(6.99 mL, 70.7 mmol) was added dropwise to the reaction mixture over 14minutes, and the reaction mixture was stirred at 0° C. for 2 hours. Thereaction was quenched with 10% NH₄Cl aq. (8.6 mL). After the mixture wasstirred, the aqueous layer was separated. The organic layer wasconcentrated under the reduced pressure to obtain the title compound(23.24 g). The yield was calculated as over 99% by HPLC externalstandard method.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.18-1.88 (m, 4H), 3.58 (m, 2H), 4.18(m, 1H), 7.47 (t, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.71 (m, 2H).

Synthesis of Ethyl 5-chloro-2-(2-trifluoromethylphenyl)pentanimidoatehydrochloride

5-Chloro-2-(2-trifluoromethylphenyl)pentanenitrile (2.0 g, 7.64 mmol)was dissolved in ethanol (5.36 mL, 91.72 mmol) at room temperature undernitrogen atmosphere. Then, the solution was cooled to 0° C. Acetylchloride (4.34 mL, 61.14 mmol) was added dropwise to the solution, andthe reaction mixture was stirred at room temperature for 67 hours. Thereaction mixture was cooled to 10° C. Traces of seed crystal of thetitle compound which was obtained by the method similar to this step andtert-butylmethylether (hereinafter referred to as “MTBE”) (40 mL) wereadded to the reaction mixture and the reaction mixture was stirred. Thesolid was collected by filtration, washed with MTBE to obtain the titlecompound (2.14 g, 81.6% yield).

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.38 (t, 3H, J=7.2 Hz), 1.78-1.65 (m,1H), 1.95-1.83 (m, 1H), 2.43-2.32 (m, 1H), 2.65-2.50 (m, 1H), 3.62-3.55(m, 2H), 4.47 (t, 1H, J=8 Hz), 4.65 (q, 2H, J=7.2 Hz), 7.47 (t, 1H,J=8.0 Hz), 7.66 (t, 1H, J=8.0 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.85 (d, 1H,J=8.0 Hz), 12.05 (brs, 1H), 12.58 (brs, 1H).

Synthesis of tert-Butyl2-{(2E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]prop-2-enoyl}hydrazinecarboxylate

DMF (52 mL) was added to the6-Bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (13.0 g, 48.5mmol) and the tert-Butyl 2-acryloylhydrazinecarboxylate (9.9 g, 53.3mmol) at room temperature under nitrogen atmosphere, And the mixture wasstirred at 50° C. for 10 minutes. Tri(o-tolyl)phosphine (885 mg, 2.90mmol), Palladium (II) acetate (327 mg, 1.45 mmol) andN,N-diisopropylethylamine (12.7 mL, 72.7 mmol) were added to themixture, and the reaction mixture was stirred at 100° C. for 4 hours.The reaction mixture was cooled to room temperature and filtratedthrough Celite. The residue was washed twice with DMF (6 mL). Water (104mL) was added dropwise to the filtrate at room temperature over 10minutes. The mixture was stirred at room temperature for 15 hours. Afterthe mixture was filtrated, the residue was washed with water/DMF=2:1 (30mL) and MTBE (30 mL). The obtained solid was suspended in MTBE (50 mL)at room temperature for 2 hours, filtrated and dried under the reducedpressure to obtain the title compound (15.8 g, 87% yield).

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.50 (s, 9H), 2.28 (d, J=1.2 Hz, 3H),4.03 (s, 3H), 6.83 (brs, 1H), 6.97-7.02 (m, 3H), 7.51 (d, J=8.0 Hz, 1H),7.59 (d, J=15.2 Hz, 1H), 7.82 (s, 1H), 8.01 (br s, 1H).

Synthesis of(2E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylohydrazidedihydrochloride

Conc. HCl (5.85 mL) was added to the suspension of tert-Butyl2-{(2E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]prop-2-enoyl}hydrazinecarboxylate(1.17 g, 3.13 mmol) in methanol (5.85 mL) with an ice-bath cooling. Thereaction mixture was stirred at room temperature for 30 minutes.1-Butanol (5.85 mL) and MTBE (5.85 mL) were added to the reactionmixture, and the mixture was stirred for 20 minutes with an ice-bathcooling. The mixture was filtrated, and the residue was washed with1-butanol-MTBE (2:8) (5.85 mL) and dried under the reduced pressure toobtain the title compound (937 mg, 78.2% yield).

¹H NMR (100 MHz, d₆-DMSO) δ (ppm): 2.36 (d, J=0.8 Hz, 3H), 3.82 (brs,2H), 4.04 (s, 3H), 7.28 (d, J=15.2 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.70(d, J=15.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 8.15 (d, J=7.6 Hz), 9.44 (d,J=1.6 Hz, 1H), 11.56 (s, 1H).

Synthesis of2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

Imidazole (4.75 g, 69.7 mmol) and Ethyl5-chloro-2-(2-trifluoromethylphenyl)pentanimidoate hydrochloride (2.00g, 5.81 mmol) were added the solution of(2E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylohydrazidedihydrochloride in methanol (10 mL) at 0° C. under nitrogen atmosphere.The reaction mixture was stirred at 30° C. for 40 hours. The reactionmixture was adjusted to the pH6.5 with 5N HCl aq., and extracted withethyl acetate (22 mL). The organic layer was washed with water (4 mL),concentrated under the reduced pressure and azeotroped with 2-propanolunder the reduced pressure to obtain the title compound (2.4 g, 86%yield). Traces of seed crystal of the title compound which was obtainedby the method similar to this step was added to the solution of thecrude title compound in 2-propanol (10 mL), and the mixture was stirredat room temperature for 13.5 hours. The suspension was stirred for 2hours with an ice-bath cooling. The solids were collected by filtrationand washed with 2-propanol and dried under the reduced pressure toobtain the title compound (1.55 g, 56% yield).

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (d,J=1.2 Hz, 3H), 2.42-2.51 (m, 1H), 4.03 (s, 3H), 4.28-4.41 (m, 2H), 4.70(dd, J=8.4, 6.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.95 (t, J=1.2 Hz, 1H),7.01 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H),7.45 (d, J=8.0 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H),7.72 (d, J=7.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).

Synthesis of(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(2S,3S)-2,3-bis(benzoyloxy)succinate (1/1)

2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(100 mg, 0.208 mmol) was dissolved in the mixture of 2-propanol (1.6 mL)and acetonitrile (2.0 mL) at 45° C., and the solution of(2S,3S)-2,3-bis(benzoyloxy)succinic acid (D-DBTA) (89.5 mg, 0.250 mmol)in acetonitrile (1.6 mL) was added. Traces of seed crystal of the titlecompound which was obtained by the method similar to this step was addedto the solution at 33° C., and the mixture was stirred at roomtemperature for 18 hours. The solids were collected by filtration,washed with acectonitrile/2-propanol=2/1 (0.5 mL) and dried at 50° C.under the reduced pressure to obtain the title compound (62.3 mg, 35.7%yield, 90.7% de). The title compound (50.7 mg, 90.7% de) was suspendedin acectonitrile/2-propanol=1/1 (0.5 mL), and the mixture was stirred at80° C. for 25 minutes, and then stirred at room temperature for 15hours. The solids were collected by filtration and dried at 50° C. underthe reduced pressure to obtain the title compound (35.9 mg, 70.8% yield,98.1% de)

¹H NMR (400 MHz, CDCl3) δ (ppm): 1.90-2.00 (1H, m), 2.12-2.20 (1H, m),2.15 (3H, s), 2.27-2.32 (2H, m), 3.98 (3H, s), 4.27-4.31 (2H, m),4.48-4.52 (1H, dd, J=5.9, 9.5 Hz), 5.84 (2H, s), 7.24-7.34 (4H, m),7.44-7.51 (2H, m), 7.56-7.63 (5H, m), 7.69-7.80 (4H, m), 7.96-8.00 (5H,m).

Synthesis of(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(2S,3S)-2,3-bis(benzoyloxy)succinate (1/1) (20 mg, 0.024 mmol) was addedto the mixed solution of ethyl acetate (0.1 mL) and 5N HCl aq. (0.1 mL),and the organic layer was separated. Ethyl acetate (0.2 mL) and 5Nsodium hydrate aq. (0.1 mL) were added to the aqueous layer, and theorganic layer was separated. The organic layer was washed twice withwater (0.1 mL), and dried under the reduced pressure to obtain the titlecompound (11.5 mg, 99.9% yield).

Synthesis of(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine(2S,3S)-tartarate (2/3)

(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineand D-tartaric acid (48.4 mg, 0.323 mmol) were solved in 1-butanol (2.0mL) at 70° C. The solution was cooled to 60° C., and then 1-butanol (1.0mL) was added. The mixture was stirred at 8° C. for 11 hours. The solidswere collected by filtration, washed with 1-butanol/n-heptan=1/2 (5.0mL) and dried at 50° C. for 3 hours to obtain the title compound (127.1mg, 86.6% yield).

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.94-1.99 (1H, m), 2.14 (3H, d, J=1.0Hz), 2.14-2.17 (2H, m), 2.27-2.32 (1H, m), 3.98 (3H, s), 4.26-4.31 (2H,m), 4.29 (3H, s), 4.48-4.52 (1H, m), 7.22-7.33 (4H, m), 7.43-7.51 (2H,m), 7.59-7.63 (1H, m), 7.56-7.79 (2H, m), 7.90 (1H, d, J=1.0 Hz).

Test Example 1 Quantification of Aβ Peptide in Culture of Neurons fromRat Fetus Brain

The present inventors performed the following tests in order to exhibitutility of the compound of the general formula (I) of the presentinvention.

(1) Rat Primary Neuronal Culture

Primary neuronal cultures were prepared from the cerebral cortex ofembryonic day 18 Wistar rats (Charles River Japan, Yokohama, Japan).Specifically, the embryos were aseptically removed from pregnant ratsunder ether anesthesia. The brain was isolated from the embryo andimmersed in an ice-cold L-15 medium (Invitrogen Corp. Cat #11415-064,Carlsbad, Calif., USA, or SIGMA L1518, for example). The cerebral cortexwas collected from the isolated brain under a stereoscopic microscope.The cerebral cortex fragments collected were enzymatically treated in anenzyme solution containing 0.25% trypsin (Invitrogen Corp. Cat#15050-065, Carlsbad, Calif., USA) and 0.01% DNase (Sigma D5025, St.Louis, Mo., USA) at 37° C. for 30 minutes to disperse the cells. Here,the enzymatic reaction was stopped by adding inactivated horse serum tothe solution. The enzymatically treated solution was centrifuged at1,500 rpm for five minutes to remove the supernatant. 5 to 10 ml of amedium was added to the resulting cell mass. Neurobasal medium(Invitrogen Corp. Cat #21103-049, Carlsbad, Calif., USA) supplementedwith 2% B27 supplement (Invitrogen Corp. Cat #17504-044, Carlsbad,Calif., USA), 25 μM 2-mercaptoethanol (2-ME, WAKO Cat #139-06861, Osaka,Japan), 0.5 mM L-glutamine (Invitrogen Corp. Cat #25030-081, Carlsbad,Calif., USA), and Antibiotics-Antimycotics (Invitrogen Corp. Cat#15240-062, Carlsbad, Calif., USA) was used as the medium(Neurobasal/B27/2-ME). However, the above Neurobasal medium notsupplemented with 2-ME (Neurobasal/B27) was used for the assay. Thecells were redispersed by mild pipetting of the cell mass to which themedium was added. The cell dispersion was filtered through a 40-μm nylonmesh (Cell Strainer, Cat #35-2340, Becton Dickinson Labware, FranklinLakes, N.J., USA) to remove the remaining cell mass, and thus a neuronalcell suspension was obtained. The neuronal cell suspension was dilutedwith the medium and then plated in a volume of 100 μl/well at an initialcell density of 5×10⁵ cells/cm² in a 96-well polystyrene culture platepre-coated with poly-L or D-lysine (Falcon Cat #35-3075, BectonDickinson Labware, Franklin Lakes, N.J., USA coated with poly-L-lysineusing the method shown below, or BIOCOAT™ cell environmentsPoly-D-lysine cell ware 96-well plate, Cat #35-6461, Becton DickinsonLabware, Franklin Lakes, N.J., USA). Poly-L-lysine coating was carriedout as follows. 100 μg/ml of a poly-L-lysine (SIGMA P2636, St. Louis,Mo., USA) solution was aseptically prepared with a 0.15 M borate buffer(pH 8.5). 100 μl/well of the solution was added to the 96-wellpolystyrene culture plate and incubated at room temperature for one ormore hours or at 4° C. overnight or longer. The coated 96-wellpolystyrene culture plate was washed with sterile water four or moretimes, and then dried or rinsed with, for example, sterile PBS ormedium, and used for cell plating. The plated cells were cultured in theculture plate at 37° C. in 5% CO₂-95% air for one day. Then, the totalamount of the medium was replaced with a fresh Neurobasal™/B27/2-MEmedium, and then the cells were cultured for further three days.

Addition of Compounds

The drug was added to the culture plate on Day 4 of culture as follows.The total amount of the medium was removed from the wells, and 180μl/well of Neurobasal medium not containing 2-ME and containing 2% B-27(Neurobasal/B27) was added thereto. A solution of the test compound indimethyl sulfoxide (hereinafter abbreviated as DMSO) was diluted withNeurobasal/B27 at 10-fold of the final concentration. 20 μl/well of thedilution was added to and sufficiently mixed with the medium. The finalDMSO concentration was 1% or less. Only DMSO was added to the controlgroup.

Sampling

The cells were cultured for three days after addition of the compound,and the total amount of the medium was collected. The resulting mediumwas used as an ELISA sample. The sample was not diluted for ELISAmeasurement of Aβx-42 and diluted to 5-fold with a diluent supplied withan ELISA kit for ELISA measurement of Aβx-40.

Evaluation of Cell Survival

Cell survival was evaluated by an MTT assay according to the followingprocedure. After collecting the medium, 100 μl/well of a pre-warmedmedium was added to the wells. Further, 8 μl/well of a solution of 8mg/ml of MTT (SIGMA M2128, St. Louis, Mo., USA) in D-PBS(−) (Dulbecco'sphosphate buffered Saline, SIGMA D8537, St. Louis, Mo., USA) was addedto the wells. The 96-well polystyrene culture plate was incubated in anincubator at 37° C. in 5% CO₂-95% air for 20 minutes. 100 μl/well of anMTT lysis buffer was added thereto, and MTT formazan crystals weresufficiently dissolved in the buffer in the incubator at 37° C. in 5%CO₂-95% air. Then, the absorbance at 550 nm in each well was measured.The MTT lysis buffer was prepared as follows. 100 g of SDS (sodiumdodecyl sulfate (sodium lauryl sulfate), WAKO 191-07145, Osaka, Japan)was dissolved in a mixed solution of 250 mL of N,N-dimethylformamide(WAKO 045-02916, Osaka, Japan) with 250 mL of distilled water. 350 μleach of concentrated hydrochloric acid and concentrated acetic acid werefurther added to the solution to allow the solution to have a final pHof about 4.7.

Upon measurement, wells having no cells plated and containing only themedium and MTT solution were set as background (bkg). The measuredvalues were respectively applied to the following formula includingsubtracting bkg values from them. Thus, the proportion against thecontrol group (group not treated with the drug, CTRL) (% of CTRL) wascalculated to compare and evaluate cell survival activities.% of CTRL=((A550_sample−A550_bkg)/(A550_CTRL−bkg))×100

-   (A550_sample: absorbance at 550 nm of sample well,-   A550_bkg: absorbance at 550 nm of background well,-   A550_CTRL: absorbance at 550 nm of control group well)    Aβ ELISA

For Aβ ELISA, Human/Rat β Amyloid (42) ELISA Kit Wako (#290-62601) fromWako Pure Chemical Industries, Ltd. or Human Amyloid beta (1-42) AssayKit (#27711) from IBL Co., Ltd. was used. Aβ ELISA was carried outaccording to the protocols recommended by the manufacturers (methodsdescribed in the attached documents). However, the Aβ calibration curvewas created using beta-amyloid peptide 1-42, rat (Calbiochem, #171596[Aβ₄₂]) The results are shown in Table 1 as percentage to the Aβconcentration in the medium of the control group (% of CTRL).

(2) The measurement results are shown in Tables 9, 10, 11 and 12 aspercentage to the Aβ concentration in the medium of the control group (%of CTRL).

TABLE 9 Test Aβ42 production compound reducing effect IC50 (nM) Example2 28 Example 3 48 Example 5 21 Example 7 30 Example 10 33 Example 12 135Example 19 43 Example 20 30 Example 22 25 Example 24 12 Example 45 30Example 55 28 Example 59 45 Example 61 31 Example 72 26 Example 80 29Example 94 52 Example 96 63 Example 97 38 Example 99 20 Example 102 20Example 103 32 Example 106 39 Example 108 29 Example 110 33 Example 11451 Example 116 173 Example 133 65 Example 141 36 Example 143 41 Example150 41

TABLE 10 Test Aβ42 production compound reducing effect IC50 (nM) Example156 48 Example 165 115 Example 169 22 Example 171 17 Example 173 37Example 175 38 Example 179 22 Example 183 48 Example 185 34 Example 18738 Example 189 43 Example 193 80 Example 195 17 Example 199 23 Example207 28 Example 209 20 Example 212 100 Example 215 74 Example 218 69Example 229 169 Example 232 33 Example 233 42 Example 236 39 Example 24350 Example 246 39 Example 247 45 Example 250 44 Example 252 146 Example254 50 Example 262 74 Example 271 57

TABLE 11 Test Aβ42 production compound reducing effect IC50 (nM) Example280 18 Example 282 29 Example 283 27 Example 286 8 Example 287 24Example 290 16 Example 294 26

TABLE 12 Test Aβ42 production compound reducing effect IC50(nM) Example311 11 Example 317 25 Example 319 15 Example 321 23 Example 327 20Example 329 17 Example 331 22 Example 333 10 Example 337 13 Example 33921 Example 354 37 Example 361 12 Example 362 9 Example 365 21 Example368 25 Example 371 27 Example 373 29 Example 376 28 Example 380 29Example 384 36 Example 390 26 Example 392 22

The results from Tables 9, 10, 11 and 12 confirmed that the compound ofthe present invention has an Aβ42 production reducing effect.

Accordingly, the compound of the general formula (I) or pharmaceuticallyacceptable salt thereof according to the present invention have an Aβ42production reducing effect. Thus, the present invention can particularlyprovide a prophylactic or therapeutic agent for a neurodegenerativedisease caused by Aβ such as Alzheimer's disease or Down's syndrome.

The compound of the general formula (I) of the present invention has anAβ40 and Aβ42 production reducing effect, and thus is particularlyuseful as a prophylactic or therapeutic agent for a neurodegenerativedisease caused by Aβ such as Alzheimer's disease or Down's syndrome.

1. A compound represented by formula (I-1), (I-2) or (1-3):

or a pharmacologically acceptable salt thereof, wherein X₁ represents—CR¹═CR²— (wherein R¹ and R² are the same or different and eachrepresents (1) a hydrogen atom, (2) a C1-6 alkyl group or (3) a halogenatom), and Het represents a group which may be substituted with 1 to 3substituents selected from Substituent Group A1 and is represented bythe following formula:

wherein n_(c) represents an integer of 0 to 3; Substituent Group A1: (1)a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyanogroup, (5) a nitro group, (6) a C3-8 cycloalkyl group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(7) a C2-6 alkenyl group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (8) a C2-6 alkynylgroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (9) a C3-8 cycloalkoxy group, (10) a C3-8cycloalkylthio group, (11) a formyl group, (12) a C1-6 alkylcarbonylgroup which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (13) a C1-6 alkylthio group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(14) a C1-6 alkylsulfinyl group which may be substituted with 1 to 3substituents selected from Substituent Group A2, (15) a C1-6alkylsulfonyl group which may be substituted with 1 to 3 substituentsselected from Substituent Group A2, (16) a hydroxyimino group, (17) aC1-6 alkoxyimino group, (18) a C1-6 alkyl group which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (19) a C1-6alkoxy group which may be substituted with 1 to 3 substituents selectedfrom Substituent Group A2, (20) an amino group which may be substitutedwith 1 or 2 substituents selected from Substituent Group A2, (21) acarbamoyl group which may be substituted with 1 or 2 substituentsselected from Substituent Group A2, (22) A* (wherein A* represents anaromatic hydrocarbon ring selected from a phenyl group, an indenylgroup, a naphthyl group, an azulenyl group, a heptalenyl group, afluorenyl group, a phenalenyl group, a phenanthrenyl group and ananthracenyl group, an aromatic heterocycle selected from a pyrrolylgroup, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, apyrazinyl group, a pyrazolinyl group, an imidazolyl group, an indolylgroup, an isoindolyl group, an indolizinyl group, a purinyl group, anindazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinylgroup, a phthalazinyl group, a naphthyridinyl group, a quinoxalinylgroup, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, animidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group,a phenanthridinyl group, a carbazolyl group, a perimidinyl group, aphenanthrolinyl group, a thienyl group and a benzothienyl group, a furylgroup, a pyranyl group, a cyclopentapyranyl group, a benzofuranyl groupand an isobenzofuranyl group, a thiazolyl group, an isothiazolyl group,a benzothiazolinyl group, a benzothiadiazolyl group, a phenothiazinylgroup, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, apyrazoloxazolyl group, an imidazothiazolyl group, a thienofuryl group, afuropyrrolyl group and a pyridooxazinyl group), which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (23) a 6-to 14-membered non-aromatic hydrocarbon ring which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (24) a 5-to 14-membered non-aromatic heterocycle, which may be substituted with 1to 3 substituents selected from Substituent Group A2, (25) a C2-6alkenyloxy group, (26) a C2-6 alkynyloxy group, (27) a C3-8cycloalkylsulfinyl group, (28) a C3-8 cycloalkylsulfonyl group, (29)—X-A* (wherein X represents an imino group, —O— or —S— and A* is asdefined above, wherein A* may be substituted with 1 to 3 substituentsselected from Substituent Group A2), (30) —CO-A* (wherein A* is asdefined above, which may be substituted with 1 to 3 substituentsselected from Substituent Group A2), (31) ═CH-A* (wherein A* is asdefined above, which may be substituted with 1 to 3 substituentsselected from Substituent Group A2), (32) a carboxyl group, (33) a C1-6alkoxycarbonyl group and (34) an azido group; Substituent Group A2: (1)a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyanogroup, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group,(10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a C1-6alkylcarbonyl group, (13) a C1-6 alkylthio group, (14) a C1-6alkylsulfinyl group, (15) a C1-6 alkylsulfonyl group, (16) ahydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6 alkylgroup (wherein the C1-6 alkyl group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (19) a C1-6 alkoxy group(wherein the C1-6 alkoxy group may be substituted with 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, a C1-6 alkoxy group, a phenyl group which may besubstituted with 1 to 3 halogen atoms and a pyridinyl group which may besubstituted with 1 to 3 halogen atoms), (20) an amino group which may besubstituted with 1 or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups,(21) a carbamoyl group which may be substituted with 1 or 2 C1-6 alkylgroups, (22) A* (wherein A* is as defined above), (23) a 6- to14-membered non-aromatic hydrocarbon ring, (24) a 5- to 14-memberednon-aromatic heterocycle, (25) a C2-6 alkenyloxy group, (26) a C2-6alkynyloxy group, (27) a C3-8 cycloalkylsulfinyl group, (28) a C3-8cycloalkylsulfonyl group, (29) —X-A* (wherein X represents an iminogroup, —O—, —S— or —SO2- and A* is as defined above, wherein A* may besubstituted with 1 to 3 halogen atoms), (30) —CO-A* (wherein A* is asdefined above, which may be substituted with 1 to 3 halogen atoms) and(31) ═CH-A* (wherein A* is as defined above, which may be substitutedwith 1 to 3 halogen atoms).
 2. The compound or pharmacologicallyacceptable salt thereof according to claim 1, wherein Substituent GroupA1 is selected from the group consisting of (1) a hydrogen atom, (2) ahalogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8cycloalkyl group which may be substituted with 1 to 3 substituentsselected from Substituent Group A2, (6) a C1-6 alkyl group which may besubstituted with 1 to 3 substituents selected from Substituent Group A2,(7) A*, wherein A is as defined in claim 2, which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (8) a 6- to14-membered non-aromatic hydrocarbon ring group which may be substitutedwith 1 to 3 substituents selected from Substituent Group A2, (9) a 5- to14-membered non-aromatic heterocycle which may be substituted with 1 to3 substituents selected from Substituent Group A2, (10) —X-A*, wherein Xrepresents an imino group, —O— or —S— and A* is as defined in claim 2,wherein A* may be substituted with 1 to 3 substituents selected fromSubstituent Group A2, (11) ═CH-A*, wherein A* is as defined in claim 1,which may be substituted with 1 to 3 substituents selected fromSubstituent Group A2) and (12) an azido group.
 3. The compound orpharmacologically acceptable salt thereof according to claim 1, whereinSubstituent Group A2 is selected from the group consisting of (1) ahydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group, wherein theC1-6 alkyl group may be substituted with 1 to 3 substituents selectedfrom the group consisting of a halogen atom and a C1-6 alkoxy group, and(4) a C1-6 alkoxy group, wherein the C1-6 alkoxy group may besubstituted with a halogen atom.
 4. The compound or pharmacologicallyacceptable salt thereof according to claim 1, wherein the (23) a 6- to14-membered non-aromatic hydrocarbon ring of Substituent Group A2 isselected from the group consisting of a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, acyclooctyl group, a spiro[3.4]octanyl group, a decanyl group, an indanylgroup, a 1-acenaphthenyl group, a cyclopentacyclooctenyl group, abenzocyclooctenyl group, an indenyl group, a tetrahydronaphthyl group, a6,7,8,9-tetrahydro-5H-benzocycloheptenyl group and a1,4-dihydronaphthalenyl group.
 5. The compound or pharmacologicallyacceptable salt thereof according to claim 1, wherein the (24) a 5- to14-membered non-aromatic heterocycle of Substituent Group A2 is selectedfrom the group consisting of an azetidinyl ring, a pyrrolidinyl ring, apiperidinyl ring, an azepanyl ring, an azocanyl ring, atetrahydrofuranyl ring, a tetrahydropyranyl ring, a morpholinyl ring, athiomorpholinyl ring, a piperazinyl ring, a thiazolidinyl ring, adioxanyl ring, an imidazolinyl ring, a thiazolinyl ring, a1,2-benzopyranyl ring, an isochromanyl ring, a chromanyl ring, anindolinyl ring, an isoindolinyl ring, an azaindanyl group, anazatetrahydronaphthyl group, an azachromanyl group, atetrahydrobenzofuranyl group, a tetrahydrobenzothienyl group, a2,3,4,5-tetrahydrobenzo[b]thienyl group, a3,4-dihydro-2H-benzo[b][1,4]dioxepinyl group, an indan-1-onyl group, a6,7-dihydro-5H-cyclopentapyrazinyl group, a 6,7-dihydro-5H-[1]pyridinylgroup, a 6,7-dihydro-5H-[1]pyridinyl group, a5,6-dihydro-4H-cyclopenta[b]thienyl group, a4,5,6,7-tetrahydro-benzo[b]thienyl group, a3,4-dihydro-2H-naphthale-1-onyl group, a 2,3-dihydro-isoindol-1-onylgroup, a 3,4-dihydro-2H-isoquinolin-1-onyl group and a3,4-dihydro-2H-benzo[1,4]oxapinyl group.
 6. The compound orpharmacologically acceptable salt thereof according to claim 1, whereinthe compound is selected from the group consisting of: 1)4-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,2)2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,3)2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,4)(R)-4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,5)(S)-4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,6)2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,7)4-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,8)2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,9)(R)-4-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,10)(S)-4-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,11)4-cyclohexyl-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,12)4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,13)2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,14)(R)-4-(2,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,15)(S)-4-(2,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,16)(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine,and 17)(−)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine.7. A pharmaceutical composition comprising: the compound orpharmacologically acceptable salt thereof according to claim 1 as anactive ingredient; and a pharmaceutically acceptable carrier.